Metalloenzyme inhibitor compounds

ABSTRACT

Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation Application of U.S.application Ser. No. 15/917,555, filed Mar. 9, 2018, now issued U.S.Pat. No. 10,357,493, which claims priority under 35 U.S.C. § 119(e) toU.S. Provisional Patent Application Ser. No. 62/469,565, filed Mar. 10,2017, and U.S. Provisional Patent Application Ser. No. 62/513,145, filedMay 31, 2017. The entirety of each is incorporated herein by reference.

BACKGROUND

Living organisms have developed tightly regulated processes thatspecifically import metals, transport them to intracellular storagesites and ultimately transport them to sites of use. One of the mostuseful functions of metals such as zinc and iron in biological systemsis to enable the activity of metalloenzymes. Metalloenzymes are enzymesthat incorporate metal ions into the enzyme active site and utilize themetal as a part of the catalytic process. More than one-third of allcharacterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence ofthe metal ion in the active site of the enzyme. It is well recognizedthat agents which bind to and inactivate the active site metal iondramatically decrease the activity of the enzyme. Nature employs thissame strategy to decrease the activity of certain metalloenzymes duringperiods in which the enzymatic activity is undesirable. For example, theprotein TIMP (tissue inhibitor of metalloproteases) binds to the zincion in the active site of various matrix metalloprotease enzymes andthereby arrests the enzymatic activity. The pharmaceutical industry hasused the same strategy in the design of therapeutic agents. For example,the azole antifungals fluconazole and voriconazole contain a1-(1,2,4-triazole) group that binds to the heme iron present in theactive site of the target enzyme lanosterol demethylase and therebyinactivates the enzyme. Another example includes the zinc-bindinghydroxamic acid group that has been incorporated into most publishedinhibitors of matrix metalloproteinases and histone deacetylases.Another example is the zinc-binding carboxylic acid group that has beenincorporated into most published angiotensin-converting enzymeinhibitors.

In the design of clinically safe and effective metalloenzyme inhibitors,use of appropriate metal-binding groups for any particular target andclinical indication is desirable. If a weakly binding metal-bindinggroup is utilized, potency may be ineffective. On the other hand, if avery tightly binding metal-binding group is utilized, non-selectivityfor the target enzyme versus related metalloenzymes may result. The lackof effective selectivity can be a cause for clinical toxicity due tounintended inhibition of these off-target metalloenzymes. One example ofsuch clinical toxicity is the unintended inhibition of human drugmetabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by thecurrently-available azole antifungal agents such as fluconazole andvoriconazole. It is believed that this off-target inhibition is causedprimarily by the indiscriminate binding of the currently utilized1-(1,2,4-triazole) to iron in the active site of CYP2C9, CYP2C19 andCYP3A4. Another example of this is the joint pain that has been observedin many clinical trials of matrix metalloproteinase inhibitors. Thistoxicity is considered to be related to inhibition of off-targetmetalloenzymes due to indiscriminate binding of the hydroxamic acidgroup to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a betterbalance of potency and selectivity remains an important goal and wouldbe significant in the realization of therapeutic agents and methods toaddress currently unmet needs in treating and preventing diseases,disorders and symptoms thereof.

Post-translational lysine acetylation of proteins is a critical processin regulating many cellular functions. This modification is a dynamicprocess controlled by two enzyme families: histone acetyltransferases(HAT) and histone deacetylases (HDAC). HDACs are responsible for thedeacetylation of lysine residues on a variety of substrates includinghistone and non-histone (e.g. α-tubulin) proteins. There are 18mammalian HDAC enzymes which are divided into four classes based onsequence identity and catalytic activity. Class I, II, and IV HDACenzymes are Zn²⁺ dependent metalloenzymes whereas the sirtuins, HDACclass III, are nicotinomide adenine dinucleotide (NAD⁺) dependent. ClassI includes HDAC1, 2, 3, and 8 and these enzymes are primarily located inthe nucleus where they are involved in histone modification andregulation of gene expression. Class II is divided into two subgroups:class IIa containing HDAC4, 5, 7, and 9 and class IIB containing HDAC6and 10. Class IV is made up of only HDAC11 (Mazitschek et al., Nat ChemBio. 2010, 6, 238-243).

For many years, HDAC enzymes have been targeted with small moleculeinhibitors due to their therapeutic potential in oncology, neurology,immunology, and infections (Kuilenburg et al., Biochem J, 2003, 370,737-749; Johnstone et al., Nature Reviews Drug Discovery, 2014, 13,673-691). Many HDAC inhibitors have progressed into clinical developmentfor the treatment of cancer but there has been limited success with theapproval of only a few pan-HDAC inhibitors (SAHA, Belinostat andPanobinostat) and the class I selective romidepsin (Wang et al.,Molecules, 2015, 20, 3898-3941). A challenge to develop HDAC inhibitorshas been the management of toxicities, many of which are dose limitingin the clinic (Piekarz et al., Pharmaceuticals, 2010, 3, 2751-2767; Wittet al., Cancer Letters, 2009, 277, 8-21). Some of the side effects canbe attributed to the hydroxamic acid metal-binding group, a common motifin many of the HDAC inhibitors. The hydroxamic acid is a potent metalbinding group that has been associated with toxicity alone but use ofthis metal binding group amplifies the problem by leading to limitedHDAC isoform selectivity and poor pharmacokinetic properties (Kozikowskiet al., Chem Med Chem, 2016, 11, 15-21; Deprez-Poulain et al., J MedChem, 2009, 52, 6790-6802).

Efforts in recent years have been focused on the pharmacology associatedwith the different HDAC classes and specific isoforms. HDAC6 is anisoform that has been of particular interest partly because it has beenshown that mice deficient in HDAC6 are viable and develop normally(Matthias et al., Molecular and Cellular Biology, 2008, 28, 1688-1701).This is in stark contrast to the lethality associated with HDAC1, 2, and3 knock outs (Witt et al., Cancer Letters, 2009, 277, 8-21). HDAC6 is aclass IIb enzyme that has a unique protein structure containing twocatalytic domains, nuclear localization and export signal sequences, acytoplasmic retention domain, and a ubiquitin binding domain. HDAC6 isalso the largest HDAC enzyme with 1215 amino acids. HDAC6 ispredominantly located in the cytoplasm except in certain instances andhas been shown to have many different non-histone protein substratesincluding α-tubulin, HSP90, cortactin, Foxp3, etc. HDAC6 inhibitors areexpected to have significant therapeutic potential in oncology,immunology, and neurology (Kalin et al., J Med Chem, 2013, 56,6297-6313; Diederich et al., Epigenomics, 2015, 7, 103-118).

There has been significant research focused on the discovery ofselective HDAC6 inhibitors but reported inhibitors still retain moderateto strong inhibition of one or more off-target HDAC isoforms. The lackof selectivity for HDAC6 leads to mixed and often difficult to interpretresults in preclinical models. There is a significant need for thedevelopment of non-hydroxamic acid HDAC6 inhibitors with an improvedpharmacokinetic profile that have selectivity over class I and otherclass II HDAC isoforms.

BRIEF SUMMARY OF THE INVENTION

The invention is directed towards compounds (e.g., any of thosedelineated herein), methods of modulating activity of metalloenzymes,and methods of treating diseases, disorders or symptoms thereof. Themethods can comprise the compounds herein.

It is understood that the embodiments of the invention discussed belowwith respect to the preferred variable selections can be taken alone orin combination with one or more embodiments, or preferred variableselections, of the invention, as if each combination were explicitlylisted herein.

In one aspect, provided are compounds of Formula I:

or pharmaceutically acceptable salts, co-crystals, tautomers,stereoisomers, solvates, hydrates, polymorphs, isotopically enrichedderivatives, or prodrugs thereof, wherein:

A is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, oralkyl, wherein A is optionally substituted with 1-3 independentsubstituents R⁵;

X is NR⁴ or O;

each of R¹ and R² is, independently, hydrogen, cyano, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein R¹ and R² are optionallysubstituted with 1-3 independent substituents R⁵;

or R¹ and R² together with the atoms to which they are attached form aheterocycloalkyl or cycloalkyl ring, wherein said heterocycloalkyl andcycloalkyl are optionally substituted with 1-3 independent substituentsR⁵;

or R¹ and A together with the atoms to which they are attached form aheterocycloalkyl ring or fused bicyclic ring;

R³ is haloalkyl or —OR^(g);

R⁴ is hydrogen or alkyl;

each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, —NR^(a)R^(b), —NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b),—(CH₂)_(n)C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d),—S(O)₂R^(d), —CO₂R^(e), COR^(f), —(CR^(e)R^(f))_(n)OR^(f), —OR^(f), oraryl substituted with 0-3 independent halogen, —NR^(a)R^(b),—NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b), —(CH₂)_(n)C(O)NR^(a)R^(b),—(CH₂)_(n)NHSO₂R^(d), —S(O)R^(d), —S(O)₂R^(d), —CO₂R^(e), —COR^(f),—(CR^(e)R^(f))_(n)OR^(f), or —OR^(f); or two occurrences of R⁵, togetherwith the atoms to which they are attached, form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl ring;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each occurrence of R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is,independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protectinggroup when attached to a nitrogen atom, or an oxygen protecting groupwhen attached to an oxygen atom; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring; or R^(e)and R^(f) together with the atoms to which they are attached form acycloalkyl ring; and

R^(g) is haloalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl,heterocycloalkyl, or arylalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl.

In certain embodiments, A is aryl, heteroaryl, or cycloalkyl. In certainembodiments, A is aryl, heteroaryl, or C₃₋₆ cycloalkyl.

In certain embodiments, A is aryl or heteroaryl.

In certain embodiments, A is aryl. In certain embodiments, A is phenylor naphthyl. In certain embodiments, A is phenyl. In certainembodiments, A is unsubstituted phenyl. In certain embodiments, A isphenyl substituted with 1-3 independent substituents R⁵. In certainembodiments, A is phenyl substituted with 1-3 independent substituentsR⁵, wherein each occurrence of R⁵ is, independently, halogen, cyano,alkyl, haloalkyl, or —OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 1, 2, or 3. In certain embodiments, A is

wherein p is 1 or 2. In certain embodiments, A is

wherein p is 1. In certain embodiments, A is

wherein p is 2. In certain embodiments, A is

wherein p is 3.

In certain embodiments, A is

R^(5a) wherein R^(5a) is any group as defined for R⁵ herein, and p is 0,1, or 2. In certain embodiments, R^(5a) is halogen. In certainembodiments, R^(5a) is F, Cl, or Br. In certain embodiments, R^(5a) is For C1. In certain embodiments, R^(5a) is F. In certain embodiments,R^(5a) is Cl. In certain embodiments, R^(5a) is halogen; each occurrenceof R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f);R^(f) is alkyl or haloalkyl; and p is 0, 1, or 2. In certainembodiments, R^(5a) is F or C1; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is alkyl orhaloalkyl; and p is 0 or 1.

In certain embodiments, A is

In certain embodiments, A is

In certain embodiments, A is

In certain embodiments, A is heteroaryl. In certain embodiments, A ismonocyclic or bicyclic heteroaryl. In certain embodiments, A is bicyclicheteroaryl. In certain embodiments, A is monocyclic heteroaryl. Incertain embodiments, A is pyridyl. In certain embodiments, A is2-pyridyl, 3-pyridyl, or 4-pyridyl. In certain embodiments, A is2-pyridyl or 3-pyridyl substituted with 1-3 independent substituents R⁵,wherein each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 0 or 1. In certain embodiments, A is

wherein p is 0 or 1.

In certain embodiments, A is

In certain embodiments, A is cycloalkyl. In certain embodiments, A isC₃₋₆ cycloalkyl. In certain embodiments, A is unsubstituted C₃₋₆cycloalkyl. In certain embodiments, A is C₃₋₆ cycloalkyl substitutedwith 0-3 independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl. In certain embodiments, A is cyclopropyl. Incertain embodiments, A is cyclobutyl. In certain embodiments, A iscyclopentyl. In certain embodiments, A is cyclohexyl.

In certain embodiments, A is arylalkyl. In certain embodiments, A isbenzyl. In certain embodiments, A is benzyl substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl.

In certain embodiments, X is NR⁴; and R⁴ is hydrogen or alkyl. Incertain embodiments, X is NH. In certain embodiments, X is O.

In certain embodiments, R¹ is hydrogen, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d),—CO₂R^(e), COR^(f), or —CH₂OR^(f), wherein R¹ is optionally substitutedwith 1-3 independent substituents R⁵.

In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, —CH₂OR^(f), —C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d). In certainembodiments, R¹ is hydrogen, alkyl, haloalkyl, aryl, cycloalkyl,—CH₂OR^(f), —C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d), wherein each occurrenceof R^(a), R^(b), R^(d), and R^(f) is, independently, alkyl, haloalkyl,or aryl; or R^(a) and R^(b) together with the atoms to which they areattached form a heterocycloalkyl ring.

In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f).In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f);and R^(f) is alkyl, haloalkyl, or aryl.

In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f). Incertain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f); and R^(f) isalkyl, haloalkyl, or aryl.

In certain embodiments, R¹ is alkyl. In certain embodiments, R¹ is C₁₋₆alkyl. In certain embodiments, R¹ is C₁₋₄ alkyl. In certain embodiments,R¹ is methyl, ethyl, propyl, butyl, isopropyl, or isobutyl. In certainembodiments, R¹ is methyl. In certain embodiments, R¹ is ethyl.

In certain embodiments, R¹ is —CH₂OR^(f). In certain embodiments, R¹ is—CH₂OR^(f); and R^(f) is hydrogen, alkyl, haloalkyl, arylalkyl, or aryl.In certain embodiments, R¹ is —CH₂OH, —CH₂O CH₂Ph, or —CH₂OCH₃.

In certain embodiments, R¹ is haloalkyl. In certain embodiments, R¹ isC₁₋₆ haloalkyl. In certain embodiments, R¹ is C₁₋₃ haloalkyl. In certainembodiments, R¹ is —CH₂F, —CF₂H, —CF₃, or —CH₂CF₃. In certainembodiments, R¹ is —CF₃ or —CH₂CF₃.

In certain embodiments, R¹ is —(CH₂)_(n)NR^(d)SO₂R^(d). In certainembodiments, R¹ is —(CH₂)_(n)NR^(d)SO₂R^(d); and each occurrence ofR^(d) is, independently, hydrogen, aryl, heteroaryl, cycloalkyl, oralkyl. In certain embodiments, R¹ is —(CH₂)_(n)NHSO₂R^(d). In certainembodiments, R¹ is —(CH₂)_(n)NHSO₂R^(d), wherein R^(d) is aryl,heteroaryl, cycloalkyl, or alkyl. In certain embodiments, R¹ is—CH₂NHSO₂R^(d), wherein R^(d) is aryl or alkyl. In certain embodiments,R¹ is —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph. In certainembodiments, R¹ is —CH₂NHSO₂Me or —CH₂NHSO₂Ph.

In certain embodiments, R¹ is hydrogen, methyl, ethyl, propyl,isopropyl, phenyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh,—C(O)-morpholinyl, —C(O)NHPh, —CH₂NHSO₂Me, or —CH₂NHSO₂Ph.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a heterocycloalkyl ring or fused bicyclic ring. Incertain embodiments, R¹ and A together with the atoms to which they areattached form a heterocycloalkyl ring or fused bicyclic ring; and R² ishydrogen.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a heterocycloalkyl ring. In certain embodiments, R¹and A together with the atoms to which they are attached form aheterocycloalkyl ring; and R² is hydrogen. In certain embodiments, R¹and A together with the atoms to which they are attached form apyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl ring.In certain embodiments, R¹ and A together with the atoms to which theyare attached form a pyrrolidinyl, piperidinyl, tetrahydrofuranyl, ortetrahydropyranyl ring; and R² is hydrogen.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a fused bicyclic ring. In certain embodiments, R¹ andA together with the atoms to which they are attached form a fusedbicyclic ring; and R² is hydrogen. In certain embodiments, R¹ and Atogether with the atoms to which they are attached form an indanyl ortetrahydronaphthalenyl ring. In certain embodiments, R¹ and A togetherwith the atoms to which they are attached form an indanyl ortetrahydronaphthalenyl ring; and R² is hydrogen.

In certain embodiments, R² is hydrogen, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), —(CH₂)_(n)NHSO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein R² is optionally substitutedwith 1-3 independent substituents R⁵.

In certain embodiments, R² is hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, —CH₂OR^(f), —C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d). In certainembodiments, R² is hydrogen, alkyl, haloalkyl, aryl, cycloalkyl,—CH₂OR^(f), —C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d), wherein each occurrenceof R^(a), R^(b), R^(d), and R^(f) is, independently, alkyl, haloalkyl,or aryl; or R^(a) and R^(b) together with the atoms to which they areattached form a heterocycloalkyl ring.

In certain embodiments, R² is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f).In certain embodiments, R² is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f);and R^(f) is alkyl, haloalkyl, or aryl.

In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f). Incertain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f); and R^(f) isalkyl, haloalkyl, or aryl.

In certain embodiments, R² is alkyl. In certain embodiments, R² is C₁₋₆alkyl. In certain embodiments, R² is C₁₋₄ alkyl. In certain embodiments,R² is methyl, ethyl, propyl, butyl, isopropyl, or isobutyl. In certainembodiments, R² is methyl. In certain embodiments, R² is ethyl.

In certain embodiments, R² is —CH₂OR^(f). In certain embodiments, R² is—CH₂OR^(f); and R^(f) is hydrogen, alkyl, haloalkyl, arylalkyl, or aryl.In certain embodiments, R² is —CH₂OH, —CH₂O CH₂Ph, or —CH₂OCH₃.

In certain embodiments, R² is haloalkyl. In certain embodiments, R² isC₁₋₆ haloalkyl. In certain embodiments, R² is C₁₋₃ haloalkyl. In certainembodiments, R² is —CH₂F, —CF₂H, —CF₃, or —CH₂CF₃. In certainembodiments, R² is —CF₃ or —CH₂CF₃.

In certain embodiments, R² is —(CH₂)_(n)NR^(d)SO₂R^(d). In certainembodiments, R² is —(CH₂)_(n)NR^(d)SO₂R^(d); and each occurrence ofR^(d) is, independently, hydrogen, aryl, heteroaryl, cycloalkyl, oralkyl. In certain embodiments, R² is —(CH₂)_(n)NHSO₂R^(d). In certainembodiments, R² is —(CH₂)_(n)NHSO₂R^(d), wherein R^(d) is aryl,heteroaryl, cycloalkyl, or alkyl. In certain embodiments, R² is—CH₂NHSO₂R^(d), wherein R^(d) is aryl or alkyl. In certain embodiments,R² is —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph. In certainembodiments, R² is —CH₂NHSO₂Me or —CH₂NHSO₂Ph.

In certain embodiments, R² is hydrogen, methyl, ethyl, propyl,isopropyl, phenyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh,—C(O)-morpholinyl, —C(O)NHPh, —CH₂NHSO₂Me, or —CH₂NHSO₂Ph. In certainembodiments, R² is hydrogen.

In certain embodiments, each of R¹ and R² is, independently, hydrogen,alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f), —C(O)NR^(a)R^(b),—CH₂NHSO₂R^(d). In certain embodiments, each of R¹ and R² is,independently, hydrogen, alkyl, haloalkyl, or —CH₂OR^(f).

In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f); and R² ishydrogen. In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f);and R² is hydrogen.

In certain embodiments, R¹ is methyl, haloalkyl, or —CH₂OR^(f); and R²is hydrogen. In certain embodiments, R² is alkyl, haloalkyl, or—CH₂OR^(f); and R² is hydrogen.

In certain embodiments, R¹ is methyl, ethyl, propyl, isopropyl, phenyl,—CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh, —C(O)-morpholinyl,—C(O)NHPh, —CH₂NHSO₂Me, or —CH₂NHSO₂Ph; and R² is hydrogen. In certainembodiments, R¹ is hydrogen, methyl, ethyl, propyl, isopropyl, —CH₂CF₃,trifluoromethyl, —CH₂OCH₃, or —CH₂OPh; and R² is hydrogen.

In certain embodiments, R¹ and R² together with the atoms to which theyare attached form a heterocycloalkyl or cycloalkyl ring, wherein saidheterocycloalkyl and cycloalkyl are optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R¹ and R² togetherwith the atoms to which they are attached form a heterocycloalkyl orcycloalkyl ring, wherein said heterocycloalkyl and cycloalkyl areoptionally substituted with 1-3 independent substituents R⁵, whereineach occurrence of R⁵ is, independently, halogen, aryl, or acyl.

In certain embodiments, R¹ and R² together with the atoms to which theyare attached form a heterocycloalkyl ring substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, aryl, or acyl. In certain embodiments, R¹ and R²together with the atoms to which they are attached form a piperidinering optionally substituted with aryl or acyl.

In certain embodiments, R¹ and R² together with the atoms to which theyare attached form a cycloalkyl ring. In certain embodiments, R¹ and R²together with the atoms to which they are attached form a cycloalkylring optionally substituted with 1-3 independent substituents R⁵. Incertain embodiments, R¹ and R² together with the atoms to which they areattached form a cycloalkyl ring optionally substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is halogen.In certain embodiments, R¹ and R² together with the atoms to which theyare attached form a C₃₋₆ cycloalkyl ring. In certain embodiments, R¹ andR² together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring optionally substituted with 1-3 independent substituentsR⁵. In certain embodiments, R¹ and R² together with the atoms to whichthey are attached form a C₃₋₆ cycloalkyl ring optionally substitutedwith 1-3 independent substituents R⁵, wherein each occurrence of R⁵ ishalogen. In certain embodiments, R¹ and R² together with the atoms towhich they are attached form a C3-4 cycloalkyl ring. In certainembodiments, R¹ and R² together with the atoms to which they areattached form a C3-4 cycloalkyl ring optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R¹ and R² togetherwith the atoms to which they are attached form a C3-4 cycloalkyl ringoptionally substituted with 1-3 independent substituents R⁵, whereineach occurrence of R⁵ is halogen.

In certain embodiments, R³ is haloalkyl. In certain embodiments, R³ isC₁₋₆ haloalkyl. In certain embodiments, R³ is C₁₋₄ haloalkyl. In certainembodiments, R³ is C₁₋₃ haloalkyl. In certain embodiments, R³ is C₁₋₂haloalkyl. In certain embodiments, R³ is —CF₃, —CHF₂, or CH₂F.

In certain embodiments, the compound of Formula I is a compound ofFormula I-a:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R³, and A are as definedherein.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl. In certain embodiments of the compound of Formula I-a, A isphenyl. In certain embodiments of the compound of Formula I-a, A isphenyl substituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-a, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-a, R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring.

In certain embodiments of the compound of Formula I-a, R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl; R¹ is alkyl, haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl,or haloalkyl; R² is hydrogen; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl; R¹ and R² together with the atoms to which they are attachedform a C₃₋₆ cycloalkyl ring; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; R¹ is alkyl, haloalkyl, or—CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; R² is hydrogen; and R³is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; R¹ and R² together with the atomsto which they are attached form a C₃₋₆ cycloalkyl ring; and R³ ishaloalkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula I-b:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R¹, R²,R³, and R⁵ are as defined herein.

In certain embodiments of the compound of Formula I-b, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-b, R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring.

In certain embodiments of the compound of Formula I-b, R³ is haloalkyl.

In certain embodiments of the compound of Formula I-b, each R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-b, R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; R²is hydrogen; R³ is haloalkyl; and each R⁵ is, independently, halogen,cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-b, R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring; R³ is haloalkyl; and each R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments, the compound of Formula I is a compound ofFormula I-c:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R³ and A are as defined herein.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl. In certain embodiments of the compound of Formula I-a, A isphenyl. In certain embodiments of the compound of Formula I-a, A isphenyl substituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-c, R³ is haloalkyl.In certain embodiments of the compound of Formula I-c, R³ is C₁₋₃haloalkyl. In certain embodiments of the compound of Formula I-c, R³ is—CF₃, —CHF₂, or CH₂F. In certain embodiments of the compound of FormulaI-c, R³ is —CHF₂.

In certain embodiments of the compound of Formula I-c, A is aryl orheteroaryl; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-c, A is aryl orheteroaryl; and R³ is C₁₋₃ haloalkyl.

In certain embodiments of the compound of Formula I-c, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; and R³ is C₁₋₃ haloalkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula I-d:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², and A are as definedherein.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl. In certain embodiments of the compound of Formula I-a, A isphenyl. In certain embodiments of the compound of Formula I-a, A isphenyl substituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-d, R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl; R¹ is alkyl, haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl,or haloalkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl; and R¹ and R² together with the atoms to which they areattached form a C₃₋₆ cycloalkyl ring.

In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f), wherein R^(f) is haloalkyl or alkyl; R¹ is alkyl, haloalkyl, or—CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; and R¹ and R² together with theatoms to which they are attached form a C₃₋₆ cycloalkyl ring.

In certain embodiments, the compound of Formula I is a compound ofFormula I-e:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R³ andR⁵ are as defined herein.

In certain embodiments of the compound of Formula I-e, R³ is haloalkyl.In certain embodiments of the compound of Formula I-e, R³ is C₁₋₃haloalkyl. In certain embodiments of the compound of Formula I-e, R³ is—CF₃, —CHF₂, or CH₂F. In certain embodiments of the compound of FormulaI-e, R³ is —CHF₂.

In certain embodiments of the compound of Formula I-e, each occurrenceof R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f).In certain embodiments of the compound of Formula I-e, each occurrenceof R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f);and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-e, R³ is haloalkyl;and each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-e, R³ is haloalkyl;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula I-f:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein A is as defined herein.

In certain embodiments of the compound of Formula I-f, A is aryl,heteroaryl, or cycloalkyl. In certain embodiments of the compound ofFormula I-f, A is aryl or heteroaryl.

In certain embodiments of the compound of Formula I-f, A is heteroaryl.In certain embodiments of the compound of Formula I-f, A is monocyclicor bicyclic heteroaryl. In certain embodiments of the compound ofFormula I-f, A is pyridyl. In certain embodiments of the compound ofFormula I-f, A is 2-pyridyl or 3-pyridyl substituted with 1-3independent substituents R⁵; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f) is haloalkyl oralkyl In certain embodiments of the compound of Formula I-f, A is aryl.In certain embodiments of the compound of Formula I-f, A is phenyl. Incertain embodiments of the compound of Formula I-f, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-f, A is

wherein R^(5a) is halogen; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is alkyl orhaloalkyl; and p is 0, 1, or 2.

In certain embodiments, the compound of Formula I is a compound ofFormula I-g:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R⁵, and p are as definedherein.

In certain embodiments of the compound of Formula I-g, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-g, R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is haloalkyl or alkyl. In certainembodiments of the compound of Formula I-g, at least one R⁵ is halogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl; R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl, and at leastone R⁵ is halogen; R¹ is alkyl, haloalkyl, or —CH₂OR^(f), wherein R^(f)is aryl, alkyl, or haloalkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is haloalkyl or alkyl; and R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is haloalkyl or alkyl; wherein at least oneR⁵ is halogen; and R¹ and R² together with the atoms to which they areattached form a C₃₋₆ cycloalkyl ring.

In certain embodiments, the compound of Formula I is a compound ofFormula I-h:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R⁵, R^(5a), and p are asdefined herein.

In certain embodiments of the compound of Formula I-h, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-h, R¹ and R²together with the atoms to which they are attached form a C₃₋₆cycloalkyl ring.

In certain embodiments of the compound of Formula I-h, p is 0, 1, or 2.In certain embodiments of the compound of Formula I-h, p is 0 or 1.

In certain embodiments of the compound of Formula I-h, R^(5a) ishalogen. In certain embodiments of the compound of Formula I-h, R^(5a)is —F or —Cl.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f);and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f),wherein R^(f) is haloalkyl or alkyl; R¹ is alkyl, haloalkyl, or—CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f);R^(f) is haloalkyl or alkyl; and R¹ and R² together with the atoms towhich they are attached form a C₃₋₆ cycloalkyl ring.

In certain embodiments, the compound of Formula I is a compound ofFormula I-i:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein each R^(d) is, independently,hydrogen, alkyl, aryl, or heteroaryl; and A is as defined herein.

In certain embodiments of the compound of Formula I-i, A is aryl,heteroaryl, or cycloalkyl. In certain embodiments of the compound ofFormula I-i, A is aryl or heteroaryl.

In certain embodiments of the compound of Formula I-i, A is heteroaryl.In certain embodiments of the compound of Formula I-i, A is monocyclicor bicyclic heteroaryl. In certain embodiments of the compound ofFormula I-i, A is pyridyl. In certain embodiments of the compound ofFormula I-i, A is 2-pyridyl or 3-pyridyl substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl

In certain embodiments of the compound of Formula I-i, A is aryl. Incertain embodiments of the compound of Formula I-i, A is phenyl. Incertain embodiments of the compound of Formula I-i, A is phenylsubstituted with 1-3 independent substituents R⁵; each occurrence of R⁵is, independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); andR^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-i, A is

wherein R^(5a) is halogen; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is alkyl orhaloalkyl; and p is 0, 1, or 2.

In another aspect, provided are compounds of Formula I:

or pharmaceutically acceptable salts, co-crystals, tautomers,stereoisomers, solvates, hydrates, polymorphs, isotopically enrichedderivatives, or prodrugs thereof, wherein:

A is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, oralkyl, wherein A is optionally substituted with 1-3 independentsubstituents R⁵;

X is NR⁴ or O;

each of R¹ and R² is, independently, hydrogen, cyano, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein R¹ and R² are optionallysubstituted with 1-3 independent substituents R⁵;

or R¹ and R² together with the atoms to which they are attached form aheterocycloalkyl or cycloalkyl ring, wherein said heterocycloalkyl andcycloalkyl are optionally substituted with 1-3 independent substituentsR⁵;

or R¹ and A together with the atoms to which they are attached form aheterocycloalkyl ring or fused bicyclic ring;

R³ is haloalkyl or —OR^(g);

R⁴ is hydrogen or alkyl;

each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, —NR^(a)R^(b), —NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b),—(CH₂)_(n)C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d),—S(O)₂R^(d), —CO₂R^(e), —COR^(f), —(CR^(e)R^(f))_(n)OR^(f), —OR^(f), oraryl substituted with 0-3 independent halogen, —NR^(a)R^(b),—NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b), —(CH₂)_(n)C(O)NR^(a)R^(b),—(CH₂)_(n)NHSO₂R^(d), —S(O)R^(d), —S(O)₂R^(d), —CO₂R^(e), —COR^(f),—(CR^(e)R^(f))_(n)OR^(f), or —OR^(f); or two occurrences of R⁵, togetherwith the atoms to which they are attached, form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl ring;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

E is a bond, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

G is heteroaryl or heterocycloalkyl;

each occurrence of R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is,independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protectinggroup when attached to a nitrogen atom, or an oxygen protecting groupwhen attached to an oxygen atom; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring; or R^(e)and R^(f) together with the atoms to which they are attached form acycloalkyl ring; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring;

R^(g) is haloalkyl; and

each occurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, orheterocycloalkylalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, or alkyl, wherein A is optionallysubstituted with 1-3 independent substituents R⁵;

X is NR⁴ or O;

each of R¹ and R² is, independently, hydrogen, cyano, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein R¹ and R² are optionallysubstituted with 1-3 independent substituents R⁵;

or R¹ and A together with the atoms to which they are attached form aheterocycloalkyl ring or fused bicyclic ring;

R³ is haloalkyl or —OR^(g);

R⁴ is hydrogen or alkyl;

each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, —NR^(a)R^(b), —NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b),—(CH₂)_(n)C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d),—S(O)₂R^(d), —CO₂R^(e), COR^(f), —(CR^(e)R^(f))_(n)OR^(f), —OR^(f), oraryl substituted with 0-3 independent halogen, —NR^(a)R^(b),—NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b), —(CH₂)_(n)C(O)NR^(a)R^(b),—(CH₂)_(n)NHSO₂R^(d), —S(O)R^(d), —S(O)₂R^(d), —CO₂R^(e), —COR^(f),—(CR^(e)R^(f))_(n)OR^(f), or —OR^(f); or two occurrences of R⁵, togetherwith the atoms to which they are attached, form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl ring;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

E is a bond, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

G is heteroaryl or heterocycloalkyl;

each occurrence of R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is,independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protectinggroup when attached to a nitrogen atom, or an oxygen protecting groupwhen attached to an oxygen atom; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring; or R^(e)and R^(f) together with the atoms to which they are attached form acycloalkyl ring; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring;

R^(g) is haloalkyl; and

each occurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, orheterocycloalkylalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl,heterocycloalkyl, or arylalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl.

In certain embodiments, A is aryl, heteroaryl, or cycloalkyl. In certainembodiments, A is aryl, heteroaryl, or C₃₋₆ cycloalkyl.

In certain embodiments, A is aryl or heteroaryl.

In certain embodiments, A is aryl. In certain embodiments, A is phenylor naphthyl. In certain embodiments, A is phenyl. In certainembodiments, A is unsubstituted phenyl. In certain embodiments, A isphenyl substituted with 1-3 independent substituents R⁵. In certainembodiments, A is phenyl substituted with 1-3 independent substituentsR⁵, wherein each occurrence of R⁵ is, independently, halogen, cyano,alkyl, haloalkyl, or —OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 1, 2, or 3. In certain embodiments, A is

wherein p is 1 or 2. In certain embodiments, A is

wherein p is 1. In certain embodiments, A is

wherein p is 2. In certain embodiments, A is

wherein p is 3.

In certain embodiments, A is

wherein R^(5a) is any group as defined for R⁵ herein, and p is 0, 1, or2. In certain embodiments, R^(5a) is halogen. In certain embodiments,R^(5a) is F, Cl, or Br. In certain embodiments, R^(5a) is F or Cl. Incertain embodiments, R^(5a) is F. In certain embodiments, R^(5a) is Cl.In certain embodiments, R^(5a) is halogen; each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) isalkyl or haloalkyl; and p is 0, 1, or 2. In certain embodiments, R^(5a)is F or Cl; each occurrence of R⁵ is, independently, halogen, cyano,alkyl, haloalkyl, or —OR^(f); R^(f) is alkyl or haloalkyl; and p is 0 or1.

In certain embodiments, A is

In certain embodiments, A is

In certain embodiments, A is

In certain embodiments, A is heteroaryl. In certain embodiments, A ismonocyclic or bicyclic heteroaryl. In certain embodiments, A is bicyclicheteroaryl. In certain embodiments, A is monocyclic heteroaryl. Incertain embodiments, A is pyridyl. In certain embodiments, A is2-pyridyl, 3-pyridyl, or 4-pyridyl. In certain embodiments, A is2-pyridyl or 3-pyridyl substituted with 1-3 independent substituents R⁵,wherein each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 0 or 1. In certain embodiments, A is

wherein p is 0 or 1.

In certain embodiments, A is

In certain embodiments, A is cycloalkyl. In certain embodiments, A isC₃₋₆ cycloalkyl. In certain embodiments, A is unsubstituted C₃₋₆cycloalkyl. In certain embodiments, A is C₃₋₆ cycloalkyl substitutedwith 0-3 independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl. In certain embodiments, A is cyclopropyl. Incertain embodiments, A is cyclobutyl. In certain embodiments, A iscyclopentyl. In certain embodiments, A is cyclohexyl.

In certain embodiments, A is heterocycloalkyl. In certain embodiments, Ais a 4-7 membered heterocycloalkyl. In certain embodiments, A is a 4-7membered heterocycloalkyl. In certain embodiments, A is a 5-6 memberedheterocycloalkyl. In certain embodiments, A is a 5 memberedheterocycloalkyl. In certain embodiments, A is a 6 memberedheterocycloalkyl. In certain embodiments, A is oxepanyl,tetrahydropyranyl, dihydropyranyl, tetrahydrofuranyl, oxetanyl,azepanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, orazetidinyl. In certain embodiments, A is tetrahydropyranyl,tetrahydrofuranyl, piperidinyl, or pyrrolidinyl.

In certain embodiments, A is arylalkyl. In certain embodiments, A isbenzyl. In certain embodiments, A is benzyl substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl.

In certain embodiments, X is NR⁴; and R⁴ is hydrogen or alkyl. Incertain embodiments, X is NH. In certain embodiments, X is O.

In certain embodiments, R¹ is hydrogen, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein R¹ is optionally substitutedwith 1-3 independent substituents R⁵.

In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, —CH₂OR^(f), —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or—(CR^(h)R^(i))_(n)-G-SO₂R^(d). In certain embodiments, R¹ is hydrogen,alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f),—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d),or -G-SO₂R^(d). In certain embodiments, R¹ is hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R¹ is —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each occurrence ofR^(a), R^(b), and R^(d) is, independently, alkyl, haloalkyl, or aryl; orR^(a) and R^(b) together with the atoms to which they are attached forma heterocycloalkyl ring; or 2 instances of R^(d) together with the atomsto which they are attached form a heterocycloalkyl ring; E is aryl; andG is heterocycloalkyl.

In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f).In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f);and R^(f) is alkyl, haloalkyl, or aryl.

In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f). Incertain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f); and R^(f) isalkyl, haloalkyl, or aryl.

In certain embodiments, R¹ is alkyl. In certain embodiments, R¹ is C₁₋₆alkyl. In certain embodiments, R¹ is C₁₋₄ alkyl. In certain embodiments,R¹ is methyl, ethyl, propyl, butyl, isopropyl, or isobutyl. In certainembodiments, R¹ is methyl. In certain embodiments, R¹ is ethyl.

In certain embodiments, R¹ is —CH₂OR^(f). In certain embodiments, R¹ is—CH₂OR^(f); and R^(f) is hydrogen, alkyl, haloalkyl, arylalkyl, or aryl.In certain embodiments, R¹ is —CH₂OH, —CH₂O CH₂Ph, or —CH₂OCH₃.

In certain embodiments, R¹ is haloalkyl. In certain embodiments, R¹ isC₁₋₆ haloalkyl. In certain embodiments, R¹ is C₁₋₃ haloalkyl. In certainembodiments, R¹ is —CH₂F, —CF₂H, —CF₃, or —CH₂CF₃. In certainembodiments, R¹ is —CF₃ or —CH₂CF₃.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b). Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b); and Eis a bond, aryl, or heteroaryl. In certain embodiments, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b). In certain embodiments, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring.In certain embodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b). In certainembodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b); and each occurrence ofR^(a) and R^(b) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R¹ is —(CH₂)_(n)NHC(O)R^(b). In certainembodiments, R¹ is —(CH₂)_(n)NHC(O)R^(b); and R^(b) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹ is—(CH₂)_(n)NHC(O)R^(b); and R^(b) is haloalkyl or alkyl. In certainembodiments, R¹ is —CH₂NHC(O)R^(b); and R^(b) is haloalkyl or alkyl. Incertain embodiments, R¹ is —CH₂NHC(O)CF₃.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-G-SO₂R^(d). In certainembodiments, R¹ is —(CR^(h)R^(i))_(n)-G-SO₂R^(d); G is heterocycloalkylor heteroaryl; each occurrence of R^(h) and R^(i) is, independently,hydrogen, halogen, haloalkyl, or alkyl; and R^(d) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹ is—(CH₂)_(n)-G-SO₂R^(d). In certain embodiments, R¹ is—(CH₂)_(n)-G-SO₂R^(d); G is heterocycloalkyl or heteroaryl; and R^(d) ishydrogen, aryl, heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certainembodiments, R¹ is -G-SO₂R^(d). In certain embodiments, R¹ is-G-SO₂R^(d); G is heterocycloalkyl; and R^(d) is, independently, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹is -G-SO₂R^(d); G is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oraziridinyl; and R^(d) is, independently, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d). Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is abond, aryl, or heteroaryl; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d). In certainembodiments, R¹ is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d); each occurrence ofR^(h) and R^(i) is, independently, hydrogen, halogen, haloalkyl, oralkyl; and each occurrence of R^(d) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring.

In certain embodiments, R¹ is —(CH₂)_(n)-E-NR^(d)SO₂R^(d). In certainembodiments, R¹ is —(CH₂)_(n)-E-NR^(d)SO₂R^(d); E is a bond or aryl; andeach occurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R¹ is —(CH₂)_(n)NR^(d)SO₂R^(d). In certainembodiments, R¹ is —(CH₂)_(n)NR^(d)SO₂R^(d); and each occurrence ofR^(d) is, independently, hydrogen, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring. In certainembodiments, R¹ is —(CH₂)_(n)NHSO₂R^(d). In certain embodiments, R¹ is—(CH₂)_(n)NHSO₂R^(d), wherein R^(d) is aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl. In certain embodiments, R¹ is —CH₂NHSO₂R^(d),wherein R^(d) is aryl or alkyl.

In certain embodiments, R¹ is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, CH₂N(CH₂CF₃)SO₂CH₃,—CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph,

In certain embodiments, R¹ is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, CH₂N(CH₂CF₃)SO₂CH₃,—CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph, or

In certain embodiments, R¹ is —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et,—CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or—CH₂NHSO₂Ph.

In certain embodiments, R¹ is hydrogen, methyl, ethyl, propyl,isopropyl, phenyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh,—C(O)-morpholinyl, —CH₂NHC(O)CF₃, —C(O)NHPh, —CH₂NHSO₂Me, —CH₂NMeSO₂Me,—CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu,—CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a heterocycloalkyl ring or fused bicyclic ring. Incertain embodiments, R¹ and A together with the atoms to which they areattached form a heterocycloalkyl ring or fused bicyclic ring; and R² ishydrogen.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a heterocycloalkyl ring. In certain embodiments, R¹and A together with the atoms to which they are attached form aheterocycloalkyl ring; and R² is hydrogen. In certain embodiments, R¹and A together with the atoms to which they are attached form apyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl ring.In certain embodiments, R¹ and A together with the atoms to which theyare attached form a pyrrolidinyl, piperidinyl, tetrahydrofuranyl, ortetrahydropyranyl ring; and R² is hydrogen.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a fused bicyclic ring. In certain embodiments, R¹ andA together with the atoms to which they are attached form a fusedbicyclic ring; and R² is hydrogen. In certain embodiments, R¹ and Atogether with the atoms to which they are attached form an indanyl ortetrahydronaphthalenyl ring. In certain embodiments, R¹ and A togetherwith the atoms to which they are attached form an indanyl ortetrahydronaphthalenyl ring; and R² is hydrogen.

In certain embodiments, R² is hydrogen, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein R² is optionally substitutedwith 1-3 independent substituents R⁵.

In certain embodiments, R² is hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, —CH₂OR^(f), —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or—(CR^(h)R^(i))_(n)-G-SO₂R^(d). In certain embodiments, R² is hydrogen,alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f),—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d),or -G-SO₂R^(d). In certain embodiments, R² is hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R² is —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R² is —(CH₂)_(n)NR^(a)C(O)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each occurrence ofR^(a), R^(b), and R^(d) is, independently, alkyl, haloalkyl, or aryl; orR^(a) and R^(b) together with the atoms to which they are attached forma heterocycloalkyl ring; or 2 instances of R^(d) together with the atomsto which they are attached form a heterocycloalkyl ring; E is aryl; andG is heterocycloalkyl.

In certain embodiments, R² is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f).In certain embodiments, R² is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f);and R^(f) is alkyl, haloalkyl, or aryl.

In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f). Incertain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f); and R^(f) isalkyl, haloalkyl, or aryl.

In certain embodiments, R² is alkyl. In certain embodiments, R² is C₁₋₆alkyl. In certain embodiments, R² is C₁₋₄ alkyl. In certain embodiments,R² is methyl, ethyl, propyl, butyl, isopropyl, or isobutyl. In certainembodiments, R² is methyl. In certain embodiments, R² is ethyl.

In certain embodiments, R² is —CH₂OR^(f). In certain embodiments, R² is—CH₂OR^(f); and R^(f) is hydrogen, alkyl, haloalkyl, arylalkyl, or aryl.In certain embodiments, R² is —CH₂OH, —CH₂O CH₂Ph, or —CH₂OCH₃.

In certain embodiments, R² is haloalkyl. In certain embodiments, R² isC₁₋₆ haloalkyl. In certain embodiments, R² is C₁₋₃ haloalkyl. In certainembodiments, R² is —CH₂F, —CF₂H, —CF₃, or —CH₂CF₃. In certainembodiments, R² is —CF₃ or —CH₂CF₃.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b). Incertain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b); and Eis a bond, aryl, or heteroaryl. In certain embodiments, R² is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b). In certain embodiments, R² is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring.In certain embodiments, R² is —(CH₂)_(n)NR^(a)C(O)R^(b). In certainembodiments, R² is —(CH₂)_(n)NR^(a)C(O)R^(b); and each occurrence ofR^(a) and R^(b) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R² is —(CH₂)_(n)NHC(O)R^(b). In certainembodiments, R² is —(CH₂)_(n)NHC(O)R^(b); and R^(b) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R² is—(CH₂)_(n)NHC(O)R^(b); and R^(b) is haloalkyl or alkyl. In certainembodiments, R² is —CH₂NHC(O)R^(b); and R^(b) is haloalkyl or alkyl. Incertain embodiments, R² is —CH₂NHC(O)CF₃.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-G-SO₂R^(d). In certainembodiments, R² is —(CR^(h)R^(i))_(n)-G-SO₂R^(d); G is heterocycloalkylor heteroaryl; each occurrence of R^(h) and R^(i) is, independently,hydrogen, halogen, haloalkyl, or alkyl; and R^(d) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R² is—(CH₂)_(n)-G-SO₂R^(d). In certain embodiments, R² is—(CH₂)_(n)-G-SO₂R^(d); G is heterocycloalkyl or heteroaryl; and R^(d) ishydrogen, aryl, heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certainembodiments, R² is -G-SO₂R^(d). In certain embodiments, R² is-G-SO₂R^(d); G is heterocycloalkyl; and R^(d) is, independently, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R²is -G-SO₂R^(d); G is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oraziridinyl; and R^(d) is, independently, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d). Incertain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is abond, aryl, or heteroaryl; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R² is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d). In certainembodiments, R² is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d); each occurrence ofR^(h) and R^(i) is, independently, hydrogen, halogen, haloalkyl, oralkyl; and each occurrence of R^(d) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring. In certain embodiments, R² is—(CH₂)_(n)-E-NR^(d)SO₂R^(d). In certain embodiments, R² is—(CH₂)_(n)-E-NR^(d)SO₂R^(d); E is a bond or aryl; and each occurrence ofR^(d) is, independently, hydrogen, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring. In certainembodiments, R² is —(CH₂)_(n)NR^(d)SO₂R^(d).

In certain embodiments, R² is —(CH₂)_(n)NR^(d)SO₂R^(d); and eachoccurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R² is —(CH₂)_(n)NHSO₂R^(d). In certain embodiments,R² is —(CH₂)_(n)NHSO₂R^(d), wherein R^(d) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R² is—CH₂NHSO₂R^(d), wherein R^(d) is aryl or alkyl.

In certain embodiments, R² is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, CH₂N(CH₂CF₃)SO₂CH₃,—CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph,

In certain embodiments, R² is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, CH₂N(CH₂CF₃)SO₂CH₃,—CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph, or

In certain embodiments, R² is —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et,—CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or—CH₂NHSO₂Ph.

In certain embodiments, R² is hydrogen, methyl, ethyl, propyl,isopropyl, phenyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh,—C(O)-morpholinyl, —CH₂NHC(O)CF₃, —C(O)NHPh, —CH₂NHSO₂Me, —CH₂NMeSO₂Me,—CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu,—CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph. In certain embodiments, R² ishydrogen.

In certain embodiments, each of R¹ and R² is, independently, hydrogen,alkyl, haloalkyl, aryl, cycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d), or—CH₂OR^(f). In certain embodiments, each of R¹ and R² is, independently,hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f),—C(O)NR^(a)R^(b), —CH₂NR^(a)C(O)R^(b), or—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d). In certain embodiments, each of R¹and R² is, independently, hydrogen, alkyl, haloalkyl, aryl, cycloalkyl,—CH₂OR^(f), —C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d). In certain embodiments,each of R¹ and R² is, independently, hydrogen, alkyl, haloalkyl,—CH₂OR^(f), or —CH₂NHSO₂R^(d).

In certain embodiments, R¹ is alkyl, haloalkyl, aryl, cycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d), or—CH₂OR^(f); and R² is hydrogen. In certain embodiments, R¹ is alkyl,haloalkyl, aryl, cycloalkyl, —CH₂OR^(f), —C(O)NR^(a)R^(b), or—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); and R² is hydrogen. In certainembodiments, R¹ is alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f),—C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d); and R² is hydrogen. In certainembodiments, R¹ is alkyl, haloalkyl, —CH₂OR^(f), or —CH₂NHSO₂R^(d); andR² is hydrogen. In certain embodiments, R¹ is —CH₂OR^(f),—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d); and R² is hydrogen. Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or —(CR^(h)R^(i))_(n)-G-SO₂R^(d);and R² is hydrogen. In certain embodiments, R¹ is—(CH₂)_(n)NR^(a)C(O)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d);and R² is hydrogen. In certain embodiments, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d) or —(CR^(h)R^(i))_(n)-G-SO₂R^(d);and R² is hydrogen. In certain embodiments, each of R¹ is —CH₂OR^(f) or—CH₂NHSO₂R^(d); and R² is hydrogen.

In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f); and R² ishydrogen. In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f);and R² is hydrogen.

In certain embodiments, R¹ is methyl, haloalkyl, or —CH₂OR^(f); and R²is hydrogen. In certain embodiments, R² is alkyl, haloalkyl, or—CH₂OR^(f); and R² is hydrogen.

In certain embodiments, R¹ is methyl, ethyl, propyl, isopropyl, phenyl,—CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh, —C(O)-morpholinyl,—CH₂NHC(O)CF₃, —C(O)NHPh, —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et,—CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or—CH₂NHSO₂Ph; and R² is hydrogen. In certain embodiments, R¹ is—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph; and R² is hydrogen.In certain embodiments, R¹ is hydrogen, methyl, ethyl, propyl,isopropyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, or —CH₂OPh; and R² ishydrogen.

In certain embodiments, R³ is haloalkyl. In certain embodiments, R³ isC₁₋₆ haloalkyl. In certain embodiments, R³ is C₁₋₄ haloalkyl. In certainembodiments, R³ is C₁₋₃ haloalkyl. In certain embodiments, R³ is C₁₋₂haloalkyl. In certain embodiments, R³ is —CF₃, —CHF₂, or CH₂F.

In certain embodiments, the compound of Formula I is a compound ofFormula I-a:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R³, and A are as definedherein.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl. In certain embodiments of the compound of Formula I-a, A isphenyl. In certain embodiments of the compound of Formula I-a, A isphenyl substituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-a, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-a, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-a, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-a, R³ is haloalkyl.In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl; R¹ is alkyl, haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl,or haloalkyl; R² is hydrogen; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl; R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond,aryl, or heteroaryl; each occurrence of R^(d) is, independently,hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; R² is hydrogen;and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; R¹ is alkyl, haloalkyl, or—CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; R² is hydrogen; and R³is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; R² is hydrogen; and R³ is haloalkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula I-b:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R¹, R²,R³, and R⁵ are as defined herein.

In certain embodiments of the compound of Formula I-b, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-b, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-b, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-b, R³ is haloalkyl.

In certain embodiments of the compound of Formula I-b, each R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-b, R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; R²is hydrogen; R³ is haloalkyl; and each R⁵ is, independently, halogen,cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-b, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; R² is hydrogen; R³ is haloalkyl; and each R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments, the compound of Formula I is a compound ofFormula I-d:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², and A are as definedherein.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl. In certain embodiments of the compound of Formula I-d, A isphenyl. In certain embodiments of the compound of Formula I-d, A isphenyl substituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-d, R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl; R¹ is alkyl, haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl,or haloalkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl; R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond,aryl, or heteroaryl; each occurrence of R^(d) is, independently,hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f), wherein R^(f) is haloalkyl or alkyl; R¹ is alkyl, haloalkyl, or—CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f), wherein R^(f) is haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-g:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R⁵, and p are as definedherein.

In certain embodiments of the compound of Formula I-g, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-g, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is haloalkyl or alkyl. In certainembodiments of the compound of Formula I-g, at least one R⁵ is halogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl; R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl, and at leastone R⁵ is halogen; R¹ is alkyl, haloalkyl, or —CH₂OR^(f), wherein R^(f)is aryl, alkyl, or haloalkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl, and at leastone R⁵ is halogen; R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is abond, aryl, or heteroaryl; each occurrence of R^(d) is, independently,hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and R² ishydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-h:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R⁵, R^(5a), and p are asdefined herein.

In certain embodiments of the compound of Formula I-h, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-h, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-h, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-h, p is 0, 1, or 2.In certain embodiments of the compound of Formula I-h, p is 0 or 1.

In certain embodiments of the compound of Formula I-h, R^(5a) ishalogen. In certain embodiments of the compound of Formula I-h, R^(5a)is —F or —Cl.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f);and R^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f),wherein R^(f) is haloalkyl or alkyl; R¹ is alkyl, haloalkyl, or—CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f),wherein R^(f) is haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-i:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R^(d) and A are as definedherein.

In certain embodiments of the compound of Formula I-i, A is aryl,heteroaryl, or cycloalkyl. In certain embodiments of the compound ofFormula I-i, A is aryl or heteroaryl.

In certain embodiments of the compound of Formula I-i, A is heteroaryl.In certain embodiments of the compound of Formula I-i, A is monocyclicor bicyclic heteroaryl. In certain embodiments of the compound ofFormula I-i, A is pyridyl. In certain embodiments of the compound ofFormula I-i, A is 2-pyridyl or 3-pyridyl substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl

In certain embodiments of the compound of Formula I-i, A is aryl. Incertain embodiments of the compound of Formula I-i, A is phenyl. Incertain embodiments of the compound of Formula I-i, A is phenylsubstituted with 1-3 independent substituents R⁵; each occurrence of R⁵is, independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); andR^(f) is haloalkyl or alkyl. In certain embodiments of the compound ofFormula I-i, A is

wherein R^(5a) is halogen; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is alkyl orhaloalkyl; and p is 0, 1, or 2.

In certain embodiments of the compound of Formula I-i, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring. In certainembodiments of the compound of Formula I-i, each occurrence of R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, or aryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring.

In certain embodiments, the compound of Formula I is a compound ofFormula I-j:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R^(d), R^(h), n, R³, and A areas defined herein.

In certain embodiments of the compound of Formula I-j, A is aryl,heteroaryl, or cycloalkyl. In certain embodiments of the compound ofFormula I-j, A is aryl or heteroaryl.

In certain embodiments of the compound of Formula I-j, A is heteroaryl.In certain embodiments of the compound of Formula I-j, A is monocyclicor bicyclic heteroaryl. In certain embodiments of the compound ofFormula I-j, A is pyridyl. In certain embodiments of the compound ofFormula I-j, A is 2-pyridyl or 3-pyridyl substituted with 1-3independent substituents R⁵, wherein each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f)is haloalkyl or alkyl

In certain embodiments of the compound of Formula I-j, A is aryl. Incertain embodiments of the compound of Formula I-j, A is phenyl. Incertain embodiments of the compound of Formula I-j, A is phenylsubstituted with 1-3 independent substituents R⁵; each occurrence of R⁵is, independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); andR^(f) is haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-j, A is

wherein R^(5a) is halogen; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is alkyl orhaloalkyl; and p is 0, 1, or 2.

In certain embodiments of the compound of Formula I-j, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring; n is 1, 2, or 3;and R^(h) is, hydrogen, halogen, haloalkyl, or alkyl. In certainembodiments of the compound of Formula I-j, each occurrence of R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, or aryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring; n is 1, 2, or 3; and R^(h) is, hydrogen,halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-j, R³ is haloalkyl.In certain embodiments of the compound of Formula I-j, R³ is C₁₋₃haloalkyl. In certain embodiments of the compound of Formula I-j, R³ is—CF₃, —CHF₂, or CH₂F. In certain embodiments of the compound of FormulaI-j, R³ is —CHF₂.

In certain embodiments, the compound of Formula I is a compound ofFormula I-k:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R^(d), R^(h), R⁵, and p are asdefined herein.

In certain embodiments of the compound of Formula I-k, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring; and R^(h) is,hydrogen, halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-k, p is 1, 2, or 3.

In certain embodiments of the compound of Formula I-k p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is haloalkyl or alkyl. In certainembodiments of the compound of Formula I-k, at least one R⁵ is halogen.

In certain embodiments of the compound of Formula I-k, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl; R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl; or 2 instances of R^(d) together with the atoms to whichthey are attached form a heterocycloalkyl ring; and R^(h) is, hydrogen,halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-k, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is haloalkyl or alkyl, and at leastone R⁵ is halogen; R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; andR^(h) is, hydrogen, halogen, haloalkyl, or alkyl.

In another aspect, provided are compounds of Formula I:

and pharmaceutically acceptable salts, co-crystals, tautomers,stereoisomers, solvates, hydrates, polymorphs, isotopically enrichedderivatives, or prodrugs thereof, wherein:

A is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, oralkyl, wherein each A is optionally substituted with 1-3 independentsubstituents R⁵;

X is NR⁴ or O;

each of R¹ and R² is, independently, hydrogen, cyano, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,heteroarylalkyl, heterocycloalkylalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein each R¹ and R² is optionallysubstituted with 1-3 independent substituents R⁵;

or R¹ and R² together with the atoms to which they are attached form aheterocycloalkyl or cycloalkyl ring, wherein said heterocycloalkyl andcycloalkyl are optionally substituted with 1-3 independent substituentsR⁵;

or R¹ and A together with the atoms to which they are attached form aheterocycloalkyl ring or fused bicyclic ring;

R³ is haloalkyl or —OR^(g);

R⁴ is hydrogen, alkyl, —(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b),—C(O)(CR^(h)R^(i))_(n)NR^(a)R^(b),C(O)O(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b), or—(CR^(h)R^(i))_(n)OP(O)(OR^(a))₂;

each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, —NR^(a)R^(b), —NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b),—(CH₂)_(n)C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d),—S(O)₂R^(d), —CO₂R^(e), COR^(f), —(CR^(e)R^(f))_(n)OR^(f), —OR^(f), oraryl substituted with 0-3 independent halogen, —NR^(a)R^(b),—NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b), —(CH₂)_(n)C(O)NR^(a)R^(b),—(CH₂)_(n)NHSO₂R^(d), —S(O)R^(d), —S(O)₂R^(d), —CO₂R^(e), —COR^(f),—(CR^(e)R^(f))_(n)OR^(f), or —OR^(f); or two occurrences of R⁵, togetherwith the atoms to which they are attached, form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl ring;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each E is independently a bond, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl;

each G is independently heteroaryl or heterocycloalkyl;

each occurrence of R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is,independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protectinggroup when attached to a nitrogen atom, or an oxygen protecting groupwhen attached to an oxygen atom; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring; or R^(e)and R^(f) together with the atoms to which they are attached form acycloalkyl ring; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring;

R^(g) is haloalkyl; and

each occurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, orheterocycloalkylalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, or alkyl, wherein each A is optionallysubstituted with 1-3 independent substituents R⁵;

X is NR⁴ or O;

each of R¹ and R² is, independently, hydrogen, cyano, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,heteroarylalkyl, heterocycloalkylalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein each R¹ and R² is optionallysubstituted with 1-3 independent substituents R⁵;

or R¹ and A together with the atoms to which they are attached form aheterocycloalkyl ring or fused bicyclic ring;

R³ is haloalkyl or —OR^(g);

R⁴ is hydrogen, alkyl, —(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b),—C(O)(CR^(h)R^(i))_(n)NR^(a)R^(b),C(O)O(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b), or—(CR^(h)R^(i))_(n)OP(O)(OR^(a))₂;

each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, —NR^(a)R^(b), —NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b),—(CH₂)_(n)C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d),—S(O)₂R^(d), —CO₂R^(e), COR^(f), —(CR^(e)R^(f))_(n)OR^(f), —OR^(f), oraryl substituted with 0-3 independent halogen, —NR^(a)R^(b),—NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b), —(CH₂)_(n)C(O)NR^(a)R^(b),—(CH₂)_(n)NHSO₂R^(d), —S(O)R^(d), —S(O)₂R^(d), —CO₂R^(e), —COR^(f),—(CR^(e)R^(f))_(n)OR^(f), or —OR^(f); or two occurrences of R⁵, togetherwith the atoms to which they are attached, form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl ring;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each E is independently a bond, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl;

each G is independently heteroaryl or heterocycloalkyl;

each occurrence of R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is,independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protectinggroup when attached to a nitrogen atom, or an oxygen protecting groupwhen attached to an oxygen atom; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring; or R^(e)and R^(f) together with the atoms to which they are attached form acycloalkyl ring; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring;

R^(g) is haloalkyl; and

each occurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, orheterocycloalkylalkyl.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl,heterocycloalkyl, or arylalkyl, wherein each A is optionally substitutedwith 1-3 independent substituents R⁵.

In certain embodiments, A is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein each A is optionally substituted with 1-3independent substituents R⁵.

In certain embodiments, A is aryl, heteroaryl, or cycloalkyl, whereineach A is optionally substituted with 1-3 independent substituents R⁵.In certain embodiments, A is aryl, heteroaryl, or C₃₋₆ cycloalkyl,wherein each A is optionally substituted with 1-3 independentsubstituents R⁵.

In certain embodiments, A is aryl or heteroaryl, wherein each A isoptionally substituted with 1-3 independent substituents R⁵.

In certain embodiments, A is aryl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, A is phenyl ornaphthyl, wherein each A is optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is phenyl optionallysubstituted with 1-3 independent substituents R⁵. In certainembodiments, A is unsubstituted phenyl. In certain embodiments, A isphenyl substituted with 1-3 independent substituents R⁵. In certainembodiments, A is phenyl substituted with 1-3 independent substituentsR⁵, wherein each occurrence of R⁵ is, independently, halogen, cyano,alkyl, haloalkyl, or —OR^(f); and each R^(f) is independently haloalkylor alkyl.

In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 1, 2, or 3. In certain embodiments, A is

wherein p is 1 or 2. In certain embodiments, A is

wherein p is 1. In certain embodiments, A is

wherein p is 2. In certain embodiments, A is

wherein p is 3.

In certain embodiments, A is

wherein R^(5a) is any group as defined for R⁵ herein, and p is 0, 1, or2. In certain embodiments, R^(5a) is halogen. In certain embodiments,R^(5a) is F, Cl, or Br. In certain embodiments, R^(5a) is F or Cl. Incertain embodiments, R^(5a) is F. In certain embodiments, R^(5a) is Cl.In certain embodiments, R^(5a) is halogen; each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) isindependently alkyl or haloalkyl; and p is 0, 1, or 2. In certainembodiments, R^(5a) is F or Cl; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is independentlyalkyl or haloalkyl; and p is 0 or 1.

In certain embodiments, A is

In certain embodiments, A is

In certain embodiments, A is

In certain embodiments, A is heteroaryl. In certain embodiments, A ismonocyclic or bicyclic heteroaryl, wherein each A is optionallysubstituted with 1-3 independent substituents R⁵. In certainembodiments, A is bicyclic heteroaryl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, A is monocyclicheteroaryl optionally substituted with 1-3 independent substituents R⁵.In certain embodiments, A is pyridyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, A is 2-pyridyl,3-pyridyl, or 4-pyridyl, wherein each A is optionally substituted with1-3 independent substituents R⁵. In certain embodiments, A is 2-pyridylor 3-pyridyl substituted with 1-3 independent substituents R⁵, whereineach occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); and R^(f) is independently haloalkyl or alkyl.

In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 0, 1, 2, or 3. In certain embodiments, A is

wherein p is 0 or 1. In certain embodiments, A is

wherein p is 0 or 1.

In certain embodiments, A is

In certain embodiments, A is cycloalkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, A is C₃₋₆cycloalkyl optionally substituted with 1-3 independent substituents R⁵.In certain embodiments, A is unsubstituted C₃₋₆ cycloalkyl. In certainembodiments, A is C₃₋₆ cycloalkyl substituted with 1-3 independentsubstituents R⁵, wherein each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f) is independentlyhaloalkyl or alkyl. In certain embodiments, A is cyclopropyl optionallysubstituted with 1-3 independent substituents R⁵. In certainembodiments, A is cyclobutyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is cyclopentyl optionallysubstituted with 1-3 independent substituents R⁵. In certainembodiments, A is cyclohexyl optionally substituted with 1-3 independentsubstituents R⁵.

In certain embodiments, A is heterocycloalkyl optionally substitutedwith 1-3 independent substituents R⁵. In certain embodiments, A is a 4-7membered heterocycloalkyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is a 4-7 memberedheterocycloalkyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is a 5-6 memberedheterocycloalkyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is a 5 memberedheterocycloalkyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is a 6 memberedheterocycloalkyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, A is oxepanyl,tetrahydropyranyl, dihydropyranyl, tetrahydrofuranyl, oxetanyl,azepanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, orazetidinyl, wherein each A is optionally substituted with 1-3independent substituents R⁵. In certain embodiments, A istetrahydropyranyl, tetrahydrofuranyl, piperidinyl, or pyrrolidinyl,wherein each A is optionally substituted with 1-3 independentsubstituents R⁵.

In certain embodiments, A is arylalkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, A is benzyloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments, A is benzyl substituted with 1-3 independent substituentsR⁵, wherein each occurrence of R⁵ is, independently, halogen, cyano,alkyl, haloalkyl, or —OR^(f); and R^(f) is independently haloalkyl oralkyl.

In certain embodiments, X is NR⁴; and R⁴ is hydrogen, alkyl,—(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b), —C(O)(CR^(h)R^(i))_(n)NR^(a)R^(b),—C(O)O(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b), or—(CR^(h)R^(i))_(n)OP(O)(OR^(a))₂. In certain embodiments, X is NR⁴; andR⁴ is hydrogen, alkyl, —(CH₂)_(n)C(O)NR^(a)R^(b),—C(O)(CH₂)_(n)NR^(a)R^(b), —C(O)O(CH₂)_(n)C(O)NR^(a)R^(b), or—(CH₂)_(n)OP(O)(OR^(a))₂. In certain embodiments, X is NR⁴; and R⁴ ishydrogen, alkyl, —CH₂C(O)NR^(a)R^(b), —C(O)CH₂NR^(a)R^(b),—C(O)OCH₂C(O)NR^(a)R^(b), or —CH₂OP(O)(OR^(a))₂; and each occurrence ofR^(a) and R^(b) is independently hydrogen or alkyl. In certainembodiments, X is NR⁴; and R⁴ is hydrogen or alkyl. In certainembodiments, X is NH. In certain embodiments, X is O.

In certain embodiments, R¹ is hydrogen, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl,heterocycloalkylalkyl, —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),C(O)NR^(a)R^(b), —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d),—(CR^(h)R^(i))_(n)-G-SO₂R^(d), —CO₂R^(e), —COR^(f), or —CH₂OR^(f),wherein each R¹ is optionally substituted with 1-3 independentsubstituents R⁵.

In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, heteroarylalkyl, heterocycloalkylalkyl, —CH₂OR^(f),—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or —(CR^(h)R^(i))_(n)-G-SO₂R^(d),wherein each R¹ is optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, R¹ is hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, heteroarylalkyl, heterocycloalkylalkyl,—CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CH₂)_(n)NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each R¹ is optionallysubstituted with 1-3 independent substituents R⁵. In certainembodiments, R¹ is hydrogen, alkyl, haloalkyl, aryl, cycloalkyl,heteroarylalkyl, heterocycloalkylalkyl, —CH₂OR^(f),—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each R¹ isoptionally substituted with 1-3 independent substituents R⁵; whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R¹ is —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each occurrence ofR^(a), R^(b), and R^(d) is, independently, alkyl, haloalkyl, or aryl; orR^(a) and R^(b) together with the atoms to which they are attached forma heterocycloalkyl ring; or 2 instances of R^(d) together with the atomsto which they are attached form a heterocycloalkyl ring; E is aryl; andG is heterocycloalkyl.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b). In certain embodiments, R¹ is—(CH₂)_(n)-G-SO₂R^(d), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or—(CH₂)_(n)-E-NR^(a)C(O)R^(b). In certain embodiments, R¹ is—(CH₂)_(n)NR^(a)C(O)R^(b), or —(CH₂)_(n)NR^(d)SO₂R^(d), wherein eachoccurrence of R^(a), R^(b), and R^(d) is, independently, alkyl,haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms to whichthey are attached form a heterocycloalkyl ring; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring.

In certain embodiments, R¹ is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f),wherein each R¹ is optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, R¹ is hydrogen, alkyl,haloalkyl, or —CH₂OR^(f); and R^(f) is alkyl, haloalkyl, cycloalkyl, oraryl.

In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f), whereineach R¹ is optionally substituted with 1-3 independent substituents R⁵.In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f); and R^(f)is alkyl, haloalkyl, cycloalkyl, or aryl.

In certain embodiments, R¹ is alkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R¹ is C₁₋₆ alkyloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments, R¹ is C₁₋₄ alkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R¹ is methyl,ethyl, propyl, butyl, isopropyl, or isobutyl. In certain embodiments, R¹is methyl. In certain embodiments, R¹ is ethyl.

In certain embodiments, R¹ is —CH₂OR^(f). In certain embodiments, R¹ is—CH₂OR^(f); and R^(f) is hydrogen, alkyl, haloalkyl, arylalkyl, or aryl.In certain embodiments, R¹ is —CH₂OH, —CH₂O CH₂Ph, —CH₂O-cyclopropyl,—CH₂OCH₂CF₃, or —CH₂OCH₃.

In certain embodiments, R¹ is haloalkyl. In certain embodiments, R¹ isC₁₋₆ haloalkyl. In certain embodiments, R¹ is C₁₋₃ haloalkyl. In certainembodiments, R¹ is —CH₂F, —CF₂H, —CF₃, or —CH₂CF₃. In certainembodiments, R¹ is —CF₃ or —CH₂CF₃.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b). Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b); and Eis a bond, aryl, or heteroaryl. In certain embodiments, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b). In certain embodiments, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring.In certain embodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b). In certainembodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b); and each occurrence ofR^(a) and R^(b) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R¹ is —(CH₂)_(n)NHC(O)R^(b). In certainembodiments, R¹ is —(CH₂)_(n)NHC(O)R^(b); and R^(b) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹ is—(CH₂)_(n)NHC(O)R^(b); and R^(b) is cycloalkyl, haloalkyl, or alkyl. Incertain embodiments, R¹ is —CH₂NHC(O)R^(b); and R^(b) is cycloalkyl,haloalkyl, or alkyl. In certain embodiments, R¹ is —CH₂NHC(O)CF₃,—CH₂NHC(O)-cyclopropyl, —CH₂N(CH₃)C(O)-cyclopropyl, —CH₂NHC(O)CH₃, or—CH₂N(CH₂CF₃)C(O)CH₃.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-G-SO₂R^(d). In certainembodiments, R¹ is —(CR^(h)R^(i))_(n)-G-SO₂R^(d); G is heterocycloalkylor heteroaryl; each occurrence of R^(h) and R^(i) is, independently,hydrogen, halogen, haloalkyl, or alkyl; and R^(d) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹ is—(CH₂)_(n)-G-SO₂R^(d). In certain embodiments, R¹ is—(CH₂)_(n)-G-SO₂R^(d); G is heterocycloalkyl or heteroaryl; and R^(d) ishydrogen, aryl, heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certainembodiments, R¹ is -G-SO₂R^(d). In certain embodiments, R¹ is-G-SO₂R^(d); G is heterocycloalkyl; and R^(d) is, independently, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹is -G-SO₂R^(d); G is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oraziridinyl; and R^(d) is, independently, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl. In certain embodiments, R¹ is —(CH₂)_(n)SO₂R^(d).In certain embodiments, R¹ is —(CH₂)_(n)SO₂R^(d), wherein R^(d) is alkylor haloalkyl. In certain embodiments, R¹ is —(CH₂)_(n)SO₂R^(d), whereinR^(d) is alkyl. In certain embodiments, R¹ is —CH₂SO₂Me.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d). Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is abond, aryl, or heteroaryl; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d). In certainembodiments, R¹ is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d); each occurrence ofR^(h) and R^(i) is, independently, hydrogen, halogen, haloalkyl, oralkyl; and each occurrence of R^(d) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring. In certain embodiments, R¹ is—(CH₂)_(n)-E-NR^(d)SO₂R^(d). In certain embodiments, R¹ is—(CH₂)_(n)-E-NR^(d)SO₂R^(d); E is a bond or aryl; and each occurrence ofR^(d) is, independently, hydrogen, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring. In certainembodiments, R¹ is —(CH₂)_(n)NR^(d)SO₂R^(d).

In certain embodiments, R¹ is —(CH₂)_(n)NR^(d)SO₂R^(d); and eachoccurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R¹ is —(CH₂)_(n)NHSO₂R^(d). In certain embodiments,R¹ is —(CH₂)_(n)NHSO₂R^(d), wherein R^(d) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R¹ is—CH₂NHSO₂R^(d), wherein R^(d) is aryl or alkyl.

In certain embodiments, R¹ is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, —CH₂N(CH₃)SO₂Et, —CH₂N(CH₂CF₃)SO₂CH₃,—CH₂N(CH₂CF₃)SO₂Et, —CH₂N(CH₃)SO₂-cyclopropyl,—CH₂N(CH₂CF₃)SO₂-cyclopropyl, —CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph,

In certain embodiments, R¹ is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, CH₂N(CH₂CF₃)SO₂CH₃,—CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph, or

In certain embodiments, R¹ is —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et,—CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or—CH₂NHSO₂Ph.

In certain embodiments, R¹ is heteroarylalkyl or heterocycloalkylalkyl,wherein each R¹ is optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, R¹ is heteroarylalkyloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments, R¹ is heterocycloalkylalkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R¹ is 5-memberedheteroarylalkyl or 5-membered heterocycloalkylalkyl, wherein each R¹ isoptionally substituted with 1-3 independent substituents R⁵. In certainembodiments, R¹ is 5-membered heteroarylalkyl optionally substitutedwith 1-3 independent substituents R⁵. In certain embodiments, R¹ is5-membered heterocycloalkylalkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R¹ ispyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl, orpyrrolidin-2-onylmethyl, wherein each R¹ is optionally substituted with1-3 independent substituents R⁵. In certain embodiments, R¹ ispyrrolylmethyl, imidazolylmethyl, or pyrazolylmethyl, wherein each R¹ isoptionally substituted with 1-3 independent substituents R⁵.

In certain embodiments, R¹ is hydrogen, methyl, ethyl, propyl,isopropyl, phenyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh,—C(O)-morpholinyl, —CH₂NHC(O)CF₃, —C(O)NHPh, —CH₂NHSO₂Me, —CH₂NMeSO₂Me,—CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu,—CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a heterocycloalkyl ring or fused bicyclic ring. Incertain embodiments, R¹ and A together with the atoms to which they areattached form a heterocycloalkyl ring or fused bicyclic ring; and R² ishydrogen.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a heterocycloalkyl ring. In certain embodiments, R¹and A together with the atoms to which they are attached form aheterocycloalkyl ring; and R² is hydrogen. In certain embodiments, R¹and A together with the atoms to which they are attached form apyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl ring.In certain embodiments, R¹ and A together with the atoms to which theyare attached form a pyrrolidinyl, piperidinyl, tetrahydrofuranyl, ortetrahydropyranyl ring; and R² is hydrogen.

In certain embodiments, R¹ and A together with the atoms to which theyare attached form a fused bicyclic ring. In certain embodiments, R¹ andA together with the atoms to which they are attached form a fusedbicyclic ring; and R² is hydrogen. In certain embodiments, R¹ and Atogether with the atoms to which they are attached form an indanyl ortetrahydronaphthalenyl ring. In certain embodiments, R¹ and A togetherwith the atoms to which they are attached form an indanyl ortetrahydronaphthalenyl ring; and R² is hydrogen.

In certain embodiments, R² is hydrogen, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein each R² is optionallysubstituted with 1-3 independent substituents R⁵.

In certain embodiments, R² is hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, —CH₂OR^(f), —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or—(CR^(h)R^(i))_(n)-G-SO₂R^(d), wherein each R² is optionally substitutedwith 1-3 independent substituents R⁵. In certain embodiments, R² ishydrogen, alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f),—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), (CH₂)_(n)NR^(d)SO₂R^(d), or-G-SO₂R^(d), wherein each R² is optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R² is hydrogen,alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f),—(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each R² isoptionally substituted with 1-3 independent substituents R⁵; whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R² is —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), whereineach occurrence of R^(a), R^(b), R^(d), and R^(f) is, independently,alkyl, haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms towhich they are attached form a heterocycloalkyl ring; or 2 instances ofR^(d) together with the atoms to which they are attached form aheterocycloalkyl ring; E is aryl; and G is heterocycloalkyl. In certainembodiments, R² is —(CH₂)_(n)NR^(a)C(O)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d), wherein each occurrence ofR^(a), R^(b), and R^(d) is, independently, alkyl, haloalkyl, or aryl; orR^(a) and R^(b) together with the atoms to which they are attached forma heterocycloalkyl ring; or 2 instances of R^(d) together with the atomsto which they are attached form a heterocycloalkyl ring; E is aryl; andG is heterocycloalkyl.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b). In certain embodiments, R² is—(CH₂)_(n)-G-SO₂R^(d), —(CH₂)_(n)-E-NR^(d)SO₂R^(d), or—(CH₂)_(n)-E-NR^(a)C(O)R^(b). In certain embodiments, R² is—(CH₂)_(n)NR^(a)C(O)R^(b) or —(CH₂)_(n)NR^(d)SO₂R^(d), wherein eachoccurrence of R^(a), R^(b), and R^(d) is, independently, alkyl,haloalkyl, or aryl; or R^(a) and R^(b) together with the atoms to whichthey are attached form a heterocycloalkyl ring; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring.

In certain embodiments, R² is hydrogen, alkyl, haloalkyl, or —CH₂OR^(f),wherein each R² is optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments, R² is hydrogen, alkyl,haloalkyl, or —CH₂OR^(f); and R^(f) is alkyl, haloalkyl, or aryl.

In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f), whereineach R² is optionally substituted with 1-3 independent substituents R⁵.In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f); and R^(f)is alkyl, haloalkyl, or aryl.

In certain embodiments, R² is alkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R² is C₁₋₆ alkyloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments, R² is C₁₋₄ alkyl optionally substituted with 1-3independent substituents R⁵. In certain embodiments, R² is methyl,ethyl, propyl, butyl, isopropyl, or isobutyl. In certain embodiments, R²is methyl. In certain embodiments, R² is ethyl.

In certain embodiments, R² is —CH₂OR^(f). In certain embodiments, R² is—CH₂OR^(f); and R^(f) is hydrogen, alkyl, haloalkyl, arylalkyl, or aryl.In certain embodiments, R² is —CH₂OH, —CH₂O CH₂Ph, —CH₂O-cyclopropyl,—CH₂OCH₂CF₃, or —CH₂OCH₃.

In certain embodiments, R² is haloalkyl. In certain embodiments, R² isC₁₋₆ haloalkyl. In certain embodiments, R² is C₁₋₃ haloalkyl. In certainembodiments, R² is —CH₂F, —CF₂H, —CF₃, or —CH₂CF₃. In certainembodiments, R² is —CF₃ or —CH₂CF₃.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b). Incertain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b); and Eis a bond, aryl, or heteroaryl. In certain embodiments, R² is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b). In certain embodiments, R² is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring.In certain embodiments, R² is —(CH₂)_(n)NR^(a)C(O)R^(b). In certainembodiments, R² is —(CH₂)_(n)NR^(a)C(O)R^(b); and each occurrence ofR^(a) and R^(b) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) together with theatoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R² is —(CH₂)_(n)NHC(O)R^(b). In certainembodiments, R² is —(CH₂)_(n)NHC(O)R^(b); and R^(b) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R² is—(CH₂)_(n)NHC(O)R^(b); and R^(b) is haloalkyl or alkyl. In certainembodiments, R² is —CH₂NHC(O)R^(b); and R^(b) is haloalkyl or alkyl. Incertain embodiments, R² is —CH₂NHC(O)CF₃, —CH₂NHC(O)-cyclopropyl,—CH₂N(CH₃)C(O)-cyclopropyl, —CH₂NHC(O)CH₃, or —CH₂N(CH₂CF₃)C(O)CH₃.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-G-SO₂R^(d). In certainembodiments, R² is —(CR^(h)R^(i))_(n)-G-SO₂R^(d); G is heterocycloalkylor heteroaryl; each occurrence of R^(h) and R^(i) is, independently,hydrogen, halogen, haloalkyl, or alkyl; and R^(d) is aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R² is—(CH₂)_(n)-G-SO₂R^(d). In certain embodiments, R² is—(CH₂)_(n)-G-SO₂R^(d); G is heterocycloalkyl or heteroaryl; and R^(d) ishydrogen, aryl, heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certainembodiments, R² is -G-SO₂R^(d). In certain embodiments, R² is-G-SO₂R^(d); G is heterocycloalkyl; and R^(d) is, independently, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl. In certain embodiments, R²is -G-SO₂R^(d); G is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oraziridinyl; and R^(d) is, independently, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl. In certain embodiments, R² is —(CH₂)_(n)SO₂R^(d).In certain embodiments, R² is —(CH₂)_(n)SO₂R^(d), wherein R^(d) is alkylor haloalkyl. In certain embodiments, R² is —(CH₂)_(n)SO₂R^(d), whereinR^(d) is alkyl. In certain embodiments, R² is —CH₂SO₂Me.

In certain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d). Incertain embodiments, R² is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is abond, aryl, or heteroaryl; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(d) is, independently, hydrogen, aryl, heteroaryl,cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring. Incertain embodiments, R² is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d). In certainembodiments, R² is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d); each occurrence ofR^(h) and R^(i) is, independently, hydrogen, halogen, haloalkyl, oralkyl; and each occurrence of R^(d) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring. In certain embodiments, R² is—(CH₂)_(n)-E-NR^(d)SO₂R^(d). In certain embodiments, R² is—(CH₂)_(n)-E-NR^(d)SO₂R^(d); E is a bond or aryl; and each occurrence ofR^(d) is, independently, hydrogen, aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring. In certainembodiments, R² is —(CH₂)_(n)NR^(d)SO₂R^(d). In certain embodiments, R²is —(CH₂)_(n)NR^(d)SO₂R^(d); and each occurrence of R^(d) is,independently, hydrogen, aryl, heteroaryl, cycloalkyl, haloalkyl, oralkyl; or 2 instances of R^(d) together with the atoms to which they areattached form a heterocycloalkyl ring. In certain embodiments, R² is—(CH₂)_(n)NHSO₂R^(d). In certain embodiments, R² is—(CH₂)_(n)NHSO₂R^(d), wherein R^(d) is aryl, heteroaryl, cycloalkyl,haloalkyl, or alkyl. In certain embodiments, R² is —CH₂NHSO₂R^(d),wherein R^(d) is aryl or alkyl.

In certain embodiments, R² is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, —CH₂N(CH₃)SO₂Et, —CH₂N(CH₂CF₃)SO₂CH₃,—CH₂N(CH₂CF₃)SO₂Et, —CH₂N(CH₃)SO₂-cyclopropyl,—CH₂N(CH₂CF₃)SO₂-cyclopropyl, —CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph,

In certain embodiments, R² is —CH₂CH₂NHSO₂Me, —CH(CH₃)NHSO₂Me,—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂CH₂CF₃, CH₂N(CH₂CF₃)SO₂CH₃,—CH₂NHSO₂-cyclopropyl, —CH₂NHSO₂Ph, or

In certain embodiments, R² is —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et,—CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or—CH₂NHSO₂Ph.

In certain embodiments, R² is hydrogen, methyl, ethyl, propyl,isopropyl, phenyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh,—C(O)-morpholinyl, —CH₂NHC(O)CF₃, —C(O)NHPh, —CH₂NHSO₂Me, —CH₂NMeSO₂Me,—CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu,—CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph. In certain embodiments, R² ishydrogen.

In certain embodiments, each of R¹ and R² is, independently, hydrogen,cyano, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, heteroarylalkyl, heterocycloalkylalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein each R¹ and R² is optionallysubstituted with 1-3 independent substituents R⁵.

In certain embodiments, each of R¹ and R² is, independently, hydrogen,alkyl, haloalkyl, aryl, cycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d), or—CH₂OR^(f), wherein each R¹ and R² is optionally substituted with 1-3independent substituents R⁵. In certain embodiments, each of R¹ and R²is, independently, hydrogen, alkyl, haloalkyl, aryl, cycloalkyl,—CH₂OR^(f), —C(O)NR^(a)R^(b), —CH₂NR^(a)C(O)R^(b), or—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), wherein each R¹ and R² isoptionally substituted with 1-3 independent substituents R⁵. In certainembodiments, each of R¹ and R² is, independently, hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, —CH₂OR^(f), —C(O)NR^(a)R^(b), or—CH₂NHSO₂R^(d), wherein each R¹ and R² is optionally substituted with1-3 independent substituents R⁵. In certain embodiments, each of R¹ andR² is, independently, hydrogen, alkyl, haloalkyl, —CH₂OR^(f), or—CH₂NHSO₂R^(d).

In certain embodiments, R¹ is cyano, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl,heterocycloalkylalkyl, —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),—C(O)NR^(a)R^(b), (CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d),—(CR^(h)R^(i))_(n)-G-SO₂R^(d), —CO₂R^(e), —COR^(f), or —CH₂OR^(f),wherein each R¹ is optionally substituted with 1-3 independentsubstituents R⁵; and R² is hydrogen.

In certain embodiments, R¹ is alkyl, haloalkyl, aryl, cycloalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d), or—CH₂OR^(f), wherein each R¹ is optionally substituted with 1-3independent substituents R⁵; and R² is hydrogen. In certain embodiments,R¹ is alkyl, haloalkyl, aryl, cycloalkyl, —CH₂OR^(f), —C(O)NR^(a)R^(b),or —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), wherein each R¹ is optionallysubstituted with 1-3 independent substituents R⁵; and R² is hydrogen. Incertain embodiments, R¹ is alkyl, haloalkyl, aryl, cycloalkyl,—CH₂OR^(f), —C(O)NR^(a)R^(b), or —CH₂NHSO₂R^(d), wherein each R¹ isoptionally substituted with 1-3 independent substituents R⁵; and R² ishydrogen. In certain embodiments, R¹ is alkyl, haloalkyl, —CH₂OR^(f), or—CH₂NHSO₂R^(d); and R² is hydrogen. In certain embodiments, R¹ is—CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d); and R² is hydrogen. Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or —(CR^(h)R^(i))_(n)-G-SO₂R^(d);and R² is hydrogen.

In certain embodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b),—(CH₂)_(n)-E-NR^(d)SO₂R^(d), or -G-SO₂R^(d); and R² is hydrogen. Incertain embodiments, R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d) or—(CR^(h)R^(i))_(n)-G-SO₂R^(d); and R² is hydrogen. In certainembodiments, each of R¹ is —CH₂OR^(f) or —CH₂NHSO₂R^(d); and R² ishydrogen.

In certain embodiments, R¹ is —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), or—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b); and R² is hydrogen. In certainembodiments, R¹ is —(CH₂)_(n)-G-SO₂R^(d), —(CH₂)_(n)-E-NR^(d)SO₂R^(d),or —(CH₂)_(n)-E-NR^(a)C(O)R^(b); and R² is hydrogen. In certainembodiments, R¹ is —(CH₂)_(n)NR^(a)C(O)R^(b) or—(CH₂)_(n)NR^(d)SO₂R^(d); and R² is hydrogen, wherein each occurrence ofR^(a), R^(b), and R^(d) is, independently, alkyl, haloalkyl, or aryl; orR^(a) and R^(b) together with the atoms to which they are attached forma heterocycloalkyl ring; or 2 instances of R^(d) together with the atomsto which they are attached form a heterocycloalkyl ring.

In certain embodiments, R¹ is alkyl, haloalkyl, or —CH₂OR^(f); and R² ishydrogen. In certain embodiments, R² is alkyl, haloalkyl, or —CH₂OR^(f);and R² is hydrogen.

In certain embodiments, R¹ is methyl, haloalkyl, or —CH₂OR^(f); and R²is hydrogen. In certain embodiments, R² is alkyl, haloalkyl, or—CH₂OR^(f); and R² is hydrogen.

In certain embodiments, R¹ is methyl, ethyl, propyl, isopropyl, phenyl,—CH₂CF₃, trifluoromethyl, —CH₂OCH₃, —CH₂OPh, —C(O)-morpholinyl,—CH₂NHC(O)CF₃, —C(O)NHPh, —CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et,—CH₂NHSO₂Pr, —CH₂NHSO₂iPr, —CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or—CH₂NHSO₂Ph; and R² is hydrogen. In certain embodiments, R¹ is—CH₂NHSO₂Me, —CH₂NMeSO₂Me, —CH₂NHSO₂Et, —CH₂NHSO₂Pr, —CH₂NHSO₂iPr,—CH₂NHSO₂iBu, —CH₂NHSO₂-cyclopropyl, or —CH₂NHSO₂Ph; and R² is hydrogen.In certain embodiments, R¹ is hydrogen, methyl, ethyl, propyl,isopropyl, —CH₂CF₃, trifluoromethyl, —CH₂OCH₃, or —CH₂OPh; and R² ishydrogen.

In certain embodiments, R³ is haloalkyl. In certain embodiments, R³ isC₁₋₆ haloalkyl. In certain embodiments, R³ is C₁₋₄ haloalkyl. In certainembodiments, R³ is C₁₋₃ haloalkyl. In certain embodiments, R³ is C₁₋₂haloalkyl. In certain embodiments, R³ is —CF₃, —CHF₂, or CH₂F.

In certain embodiments, the compound of Formula I is a compound ofFormula I-a:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², R³, and A are as definedherein.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵. In certain embodiments of the compound ofFormula I-a, A is aryl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments of the compound of Formula I-a,A is phenyl optionally substituted with 1-3 independent substituents R⁵.In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is independently haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-a, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-a, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-a, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-a, R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl; R¹ is alkyl, haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl,or haloalkyl; R² is hydrogen; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is aryl orheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵; R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d);E is a bond, aryl, or heteroaryl; each occurrence of R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl; or 2 instances of R^(d) together with the atoms to whichthey are attached form a heterocycloalkyl ring; each occurrence of R^(h)and R^(i) is, independently, hydrogen, halogen, haloalkyl, or alkyl; R²is hydrogen; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is independently haloalkyl or alkyl; R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; R² ishydrogen; and R³ is haloalkyl.

In certain embodiments of the compound of Formula I-a, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); R^(f) is independently haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; R² is hydrogen; and R³ is haloalkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula I-b:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R¹, R²,R³, and R⁵ are as defined herein.

In certain embodiments of the compound of Formula I-b, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-b, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-b, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-b, R³ is haloalkyl.

In certain embodiments of the compound of Formula I-b, each R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-b, R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; R²is hydrogen; R³ is haloalkyl; and each R⁵ is, independently, halogen,cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments of the compound of Formula I-b, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; R² is hydrogen; R³ is haloalkyl; and each R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, or —OR^(f).

In certain embodiments, the compound of Formula I is a compound ofFormula I-d:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R¹, R², and A are as definedherein.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵. In certain embodiments of the compound ofFormula I-d, A is aryl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments of the compound of Formula I-d,A is phenyl optionally substituted with 1-3 independent substituents R⁵.In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f); and R^(f) is independently haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-d, R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵; R¹ is alkyl, haloalkyl, or —CH₂OR^(f);R^(f) is aryl, alkyl, or haloalkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is aryl orheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵; R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d);E is a bond, aryl, or heteroaryl; each occurrence of R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl; or 2 instances of R^(d) together with the atoms to whichthey are attached form a heterocycloalkyl ring; each occurrence of R^(h)and R^(i) is, independently, hydrogen, halogen, haloalkyl, or alkyl; andR² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f), wherein R^(f) is independently haloalkyl or alkyl; R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-d, A is phenylsubstituted with 1-3 independent substituents R⁵, wherein eachoccurrence of R⁵ is, independently, halogen, cyano, alkyl, haloalkyl, or—OR^(f), wherein R^(f) is independently haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-g:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R¹, R²,and R⁵ are as defined herein.

In certain embodiments of the compound of Formula I-g, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-g, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is independently haloalkyl or alkyl. Incertain embodiments of the compound of Formula I-g, at least one R⁵ ishalogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is independently haloalkyl oralkyl; R¹ is alkyl, haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl,alkyl, or haloalkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is independently haloalkyl oralkyl, and at least one R⁵ is halogen; R¹ is alkyl, haloalkyl, or—CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is independently haloalkyl oralkyl; R¹ is —(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, orheteroaryl; each occurrence of R^(d) is, independently, hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d)together with the atoms to which they are attached form aheterocycloalkyl ring; each occurrence of R^(h) and R^(i) is,independently, hydrogen, halogen, haloalkyl, or alkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-g, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is independently haloalkyl oralkyl, and at least one R⁵ is halogen; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-h:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R¹, R²,R⁵, and R^(5a) are as defined herein.

In certain embodiments of the compound of Formula I-h, R¹ is alkyl,haloalkyl, or —CH₂OR^(f); R^(f) is aryl, alkyl, or haloalkyl; and R² ishydrogen.

In certain embodiments of the compound of Formula I-h, R¹ is—(CR^(h)R^(i))_(n)NR^(a)C(O)R^(b); each occurrence of R^(h) and R^(i)is, independently, hydrogen, halogen, haloalkyl, or alkyl; and eachoccurrence of R^(a) and R^(b) is, independently, hydrogen, aryl,heteroaryl, cycloalkyl, haloalkyl, or alkyl; or R^(a) and R^(b) togetherwith the atoms to which they are attached form a heterocycloalkyl ring;and R² is hydrogen.

In certain embodiments of the compound of Formula I-h, R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments of the compound of Formula I-h, p is 0, 1, or 2.In certain embodiments of the compound of Formula I-h, p is 0 or 1.

In certain embodiments of the compound of Formula I-h, R^(5a) ishalogen. In certain embodiments of the compound of Formula I-h, R^(5a)is —F or —Cl.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f);and R^(f) is independently haloalkyl or alkyl.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f),wherein R^(f) is independently haloalkyl or alkyl; R¹ is alkyl,haloalkyl, or —CH₂OR^(f), wherein R^(f) is aryl, alkyl, or haloalkyl;and R² is hydrogen.

In certain embodiments of the compound of Formula I-h, p is 0 or 1;R^(5a) is halogen; R⁵ is halogen, cyano, alkyl, haloalkyl, or —OR^(f),wherein R^(f) is independently haloalkyl or alkyl; R¹ is—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d); E is a bond, aryl, or heteroaryl;each occurrence of R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,haloalkyl, or alkyl; and R² is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-i:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R^(d) and A are as definedherein.

In certain embodiments of the compound of Formula I-i, A is aryl,heteroaryl, or cycloalkyl, wherein each A is optionally substituted with1-3 independent substituents R⁵. In certain embodiments of the compoundof Formula I-i, A is aryl or heteroaryl, wherein each A is optionallysubstituted with 1-3 independent substituents R⁵.

In certain embodiments of the compound of Formula I-i, A is heteroaryloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments of the compound of Formula I-i, A is monocyclic or bicyclicheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵. In certain embodiments of the compound ofFormula I-i, A is pyridyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments of the compound of Formula I-i,A is 2-pyridyl or 3-pyridyl substituted with 1-3 independentsubstituents R⁵, wherein each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f) is independentlyhaloalkyl or alkyl.

In certain embodiments of the compound of Formula I-i, A is aryloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments of the compound of Formula I-i, A is phenyl optionallysubstituted with 1-3 independent substituents R⁵. In certain embodimentsof the compound of Formula I-i, A is phenyl substituted with 1-3independent substituents R⁵; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f) is independentlyhaloalkyl or alkyl.

In certain embodiments of the compound of Formula I-i, A is

wherein R^(5a) is halogen; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is independentlyalkyl or haloalkyl; and p is 0, 1, or 2.

In certain embodiments of the compound of Formula I-i, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring. In certainembodiments of the compound of Formula I-i, each occurrence of R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, or aryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring.

In certain embodiments of the compound of Formula I-i, A is phenylsubstituted with halogen or —OR^(f); R^(f) is haloalkyl; and eachoccurrence of R^(d) is, independently, hydrogen, alkyl, or haloalkyl.

In certain embodiments, the compound of Formula I is a compound ofFormula I-j:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R^(d), R^(h), n, R³, and A areas defined herein.

In certain embodiments of the compound of Formula I-i, A is aryl,heteroaryl, or cycloalkyl, wherein each A is optionally substituted with1-3 independent substituents R⁵. In certain embodiments of the compoundof Formula I-i, A is aryl or heteroaryl, wherein each A is optionallysubstituted with 1-3 independent substituents R⁵.

In certain embodiments of the compound of Formula I-i, A is heteroaryloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments of the compound of Formula I-i, A is monocyclic or bicyclicheteroaryl, wherein each A is optionally substituted with 1-3independent substituents R⁵. In certain embodiments of the compound ofFormula I-i, A is pyridyl optionally substituted with 1-3 independentsubstituents R⁵. In certain embodiments of the compound of Formula I-i,A is 2-pyridyl or 3-pyridyl substituted with 1-3 independentsubstituents R⁵, wherein each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f) is independentlyhaloalkyl or alkyl.

In certain embodiments of the compound of Formula I-i, A is aryloptionally substituted with 1-3 independent substituents R⁵. In certainembodiments of the compound of Formula I-i, A is phenyl optionallysubstituted with 1-3 independent substituents R⁵. In certain embodimentsof the compound of Formula I-i, A is phenyl substituted with 1-3independent substituents R⁵; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); and R^(f) is independentlyhaloalkyl or alkyl.

In certain embodiments of the compound of Formula I-j, A is

wherein R^(5a) is halogen; each occurrence of R⁵ is, independently,halogen, cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is independentlyalkyl or haloalkyl; and p is 0, 1, or 2.

In certain embodiments of the compound of Formula I-j, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring; n is 1, 2, or 3;and R^(h) is, hydrogen, halogen, haloalkyl, or alkyl. In certainembodiments of the compound of Formula I-j, each occurrence of R^(d) is,independently, hydrogen, alkyl, haloalkyl, cycloalkyl, or aryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring; n is 1, 2, or 3; and R^(h) is, hydrogen,halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-j, R³ is haloalkyl.In certain embodiments of the compound of Formula I-j, R³ is C₁₋₃haloalkyl. In certain embodiments of the compound of Formula I-j, R³ is—CF₃, —CHF₂, or CH₂F. In certain embodiments of the compound of FormulaI-j, R³ is —CHF₂.

In certain embodiments of the compound of Formula I-j, A is phenylsubstituted with halogen or —OR^(f); R^(f) is haloalkyl; each occurrenceof R^(d) is, independently, hydrogen, alkyl, or haloalkyl; R³ is —CF₃,—CHF₂, or CH₂F; n is 1; and R^(h) is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-k:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein p is 0, 1, 2, or 3; and R^(d),R^(h), and R⁵ are as defined herein.

In certain embodiments of the compound of Formula I-k, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring; and R^(h) is,hydrogen, halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-k, p is 1, 2, or 3.

In certain embodiments of the compound of Formula I-k p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f); R^(f) is independently haloalkyl or alkyl. Incertain embodiments of the compound of Formula I-k, at least one R⁵ ishalogen.

In certain embodiments of the compound of Formula I-k, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is independently haloalkyl oralkyl; R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring; and R^(h) is,hydrogen, halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-k, p is 1, 2, or 3;each occurrence of R⁵ is, independently, halogen, cyano, alkyl,haloalkyl, or —OR^(f), wherein R^(f) is independently haloalkyl oralkyl, and at least one R⁵ is halogen; R^(d) is, independently,hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl; or 2instances of R^(d) together with the atoms to which they are attachedform a heterocycloalkyl ring; and R^(h) is, hydrogen, halogen,haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-k, p is 1; R⁵ ishalogen or —OR^(f); R^(f) is haloalkyl; each occurrence of R^(d) is,independently, hydrogen, alkyl, or haloalkyl; and R^(h) is hydrogen.

In certain embodiments, the compound of Formula I is a compound ofFormula I-i:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein R^(d), R^(h), and R⁵ are asdefined herein.

In certain embodiments of the compound of Formula I-l, each occurrenceof R^(d) is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl,aryl, or heteroaryl; or 2 instances of R^(d) together with the atoms towhich they are attached form a heterocycloalkyl ring; and R^(h) is,hydrogen, halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-l, R⁵ is halogen,cyano, alkyl, haloalkyl, or —OR^(f); R^(f) is independently haloalkyl oralkyl. In certain embodiments of the compound of Formula I-k, R⁵ ishalogen or —OR^(f); and R^(f) is haloalkyl.

In certain embodiments of the compound of Formula I-l, R⁵ is halogen,cyano, alkyl, haloalkyl, or —OR^(f), wherein R^(f) is independentlyhaloalkyl or alkyl; R^(d) is, independently, hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, or heteroaryl; or 2 instances of R^(d) together withthe atoms to which they are attached form a heterocycloalkyl ring; andR^(h) is, hydrogen, halogen, haloalkyl, or alkyl.

In certain embodiments of the compound of Formula I-l, R⁵ is halogen or—OR^(f); R^(f) is haloalkyl; each occurrence of R^(d) is, independently,hydrogen, alkyl, or haloalkyl; and R^(h) is hydrogen.

In certain embodiments, the compound of Formula I is a compound selectedfrom the group consisting of:

-   N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (2);-   N-((6-methylpyridin-2-yl)methyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (3);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylethyl)pyrimidin-2-amine    (6);-   N-benzhydryl-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (7);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-N-methylpyrimidin-2-amine    (8);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)pyrimidin-2-amine    (9);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)pyrimidin-2-amine    (11);-   2-(difluoromethyl)-5-(2-(1-phenylcyclopropoxy)pyrimidin-5-yl)-1,3,4-oxadiazole    (12);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine    (13);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine    (13(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine    (13(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropyl)pyrimidin-2-amine    (14);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-amine    (15);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropyl)pyrimidin-2-amine    (16);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(4-(4-fluorophenyl)-1-phenylpiperidin-4-yl)pyrimidin-2-amine    (17);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)pyrimidin-2-amine    (18);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-phenoxyethyl)pyrimidin-2-amine    (19);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine    (20);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine    (20(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine    (20(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methoxyethyl)pyrimidin-2-amine    (21);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)propyl)pyrimidin-2-amine    (22);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)butyl)pyrimidin-2-amine    (23);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine    (24);-   5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile    (25);-   1-(4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-(4-fluorophenyl)piperidin-1-yl)ethanone    (26);-   N-(1-cyclohexylcyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (27);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-isopropylcyclopropyl)pyrimidin-2-amine    (28);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine    (29);-   2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-1-morpholinoethanone    (30);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)ethyl)pyrimidin-2-amine    (31);-   N-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (32);-   N-(1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (33);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidin-2-amine    (34);-   2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide    (35);-   N-(cyclopropyl(4-fluorophenyl)methyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (36);-   N-(4,4-difluoro-1-(4-fluorophenyl)cyclohexyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (37);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide    (38);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide    (38(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide    (38(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide    (39);-   N-(1-(2-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (40);-   N-(1-(3-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (41);-   N-(1-(4-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (42);-   N-(1-(4-bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (47);-   4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzonitrile    (48);-   N-(1-(2-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (52);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (53);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (54);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (55);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine    (58);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,3-difluorophenyl)cyclopropyl)pyrimidin-2-amine    (60);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,5-difluorophenyl)cyclopropyl)pyrimidin-2-amine    (61);-   N-(1-(2-chloro-4-fluorophenyl)cyclopropyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (62);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluoro-2-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine    (63);-   N-(1-(6-bromopyridin-3-yl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (64);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(pyridin-3-yl)cyclopropyl)pyrimidin-2-amine    (65);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)cyclopropyl)pyrimidin-2-amine    (67);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (68);-   N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzyl)methanesulfonamide    (69);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (70);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine    (71);-   N-(1-(3-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (73);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4,6-trifluorophenyl)cyclopropyl)pyrimidin-2-amine    (74);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-5-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (75);-   N-(1-(5-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (76);-   N-(1-(2-chloro-3-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (77);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide    (78);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide    (78(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide    (78(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzamide    (79);-   N-(1-(2-chloro-5-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (80);-   N-(1-(2-chloro-5-(trifluoromethyl)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (81);-   N-(1-(2-bromopyridin-4-yl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (82);-   4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile    (83);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pyrimidin-2-amine    (84);-   N-(1-(2-chloro-3-(trifluoromethyl)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (85);-   N-(1-(2-chloro-3-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (86);-   N-(1-(2-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (87);-   N-(1-(2-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (89);-   N-(1-(2-chloro-5-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (90);-   N-(1-(2-chloro-3-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (91);-   1-(4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-isopropylpiperidin-1-yl)ethanone    (92);-   1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-1-(2,4-difluorophenyl)propan-2-ol    (93);-   Ni-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-1-(4-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine    (94);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(4-(2,4-difluorophenyl)-1-methylpiperidin-4-yl)pyrimidin-2-amine    (95);-   N1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-1-(4-fluorophenyl)ethane-1,2-diamine    (96);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(2,4-difluorophenyl)propan-2-yl)pyrimidin-2-amine    (97);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(2,6-difluorophenyl)propan-2-yl)pyrimidin-2-amine    (98);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)ethyl)pyrimidin-2-amine    (99);-   5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[(1R)-1-(2,4-difluorophenyl)ethyl]pyrimidin-2-amine    (99-R);-   5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[(1S)-1-(2,4-difluorophenyl)ethyl]pyrimidin-2-amine    (99-S);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine    (100);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine    (100(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine    (100(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-3,3,3-trifluoropropyl)pyrimidin-2-amine    (101);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)-3,3,3-trifluoropropyl)pyrimidin-2-amine    (102);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide    (103);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide    (103(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide    (103(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,6-difluorophenyl)ethyl)methanesulfonamide    (104);-   N-(1-(2-(difluoromethoxy)-6-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (105);-   N-(1-(2,6-difluoro-4-methoxyphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (106);-   N-(1-(2,6-difluoro-4-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (107);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)ethanesulfonamide    (108);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-2-sulfonamide    (109);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanesulfonamide    (110);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-1-sulfonamide    (111);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2-methylpropane-1-sulfonamide    (112);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide    (113);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide    (113(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2,2,2-trifluoroacetamide    (114);-   N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (115)-   (+)-N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (115(+));-   (−)-N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (115(−));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (116);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (116(+));-   (−)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (116(−));-   N-(2-(4-(difluoromethoxy)-2,6-difluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (117);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (118);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (118(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2,2,2-trifluoroethanesulfonamide    (119);-   2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine    1,1-dioxide (120);-   (+)-2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine    1,1-dioxide (120(+));-   (−)-2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine    1,1-dioxide (120(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4,6-trifluorophenyl)ethyl)methanesulfonamide    (121);-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide    (122);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide    (122(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide    (122(−));-   N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (123);-   (+)-N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (123(+));-   (−)-N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (123(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(tetrahydro-2H-pyran-4-yl)ethyl)methanesulfonamide    (124);-   N-(3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide    (125);-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-((4-fluorophenyl)(1-(methylsulfonyl)azetidin-3-yl)methyl)pyrimidin-2-amine    (126);-   N-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)methanesulfonamide    (127);-   N-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide    (128);-   N-(4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide    (129);-   N-(2-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide    (130);-   N-(2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide    (131);-   N-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide    (132);-   N-(4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide    (133);-   N-(2-cyclopropoxy-1-(2,4-difluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (134);-   N-(2-cyclopropoxy-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (135);-   (+)-N-(2-cyclopropoxy-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (135(+));-   (−)-N-(2-cyclopropoxy-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (135(−));-   N-(2-cyclopropoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (136);-   (+)-N-(2-cyclopropoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (136(+));-   (−)-N-(2-cyclopropoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine    (136(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide    (137);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide    (137(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (138);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (138(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide    (139);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide    (139(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide    (140);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide    (140(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (141);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (141(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide    (142);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide    (142(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide    (143);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide    (143(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (144);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (144(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide    (145);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide    (145(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (146);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (146(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide    (147);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide    (147(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide    (148);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide    (148(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (149);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (149(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide    (150);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide    (150(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide    (151);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide    (151(+));-   N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (152);-   (+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (152(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide    (153);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide    (153(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (154);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (154(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide    (155);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide    (155(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide    (156);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide    (156(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (157);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (157(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide    (158);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide    (158(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide    (159);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide    (159(+));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (160);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (160(+));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine    (161);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine    (161(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine    (161(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine    (162);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine    (162(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine    (162(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine    (163);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine    (163(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine    (163(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (164);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (164(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide    (164(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (165);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (165(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide    (165(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide    (166);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide    (166(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide    (166(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide    (167);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide    (167(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide    (167(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide    (168);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide    (168(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide    (168(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide    (169);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide    (169(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide    (169(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide    (170);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide    (170(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide    (170(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide    (171);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide    (171(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide    (171(−));-   N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (172);-   (+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (172(+));-   (−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (172(−));-   N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (173);-   (+)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (173(+));-   (−)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide    (173(−));-   N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (174);-   (+)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (174(+));-   (−)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide    (174(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine    (175);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine    (175(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine    (175(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine    (176);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine    (176(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine    (176(−));-   1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one    (177);-   (+)-1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one    (177(+));-   (−)-1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one    (177(−));-   5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(3-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl)pyrimidin-2-amine    (178);-   (+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(3-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl)pyrimidin-2-amine    (178(+));-   (−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(3-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl)pyrimidin-2-amine    (178(−));-   2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(1-(4-fluorophenyl)cyclopropyl)amino)-N,N-dimethylacetamide    (179);-   2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(1-(4-fluorophenyl)cyclopropyl)amino)-N,N-diethylacetamide    (180);-   2-(dimethylamino)-2-oxoethyl(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(l-(4-fluorophenyl)cyclopropyl)carbamate    (181);-   2-(diethylamino)-2-oxoethyl(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(l-(4-fluorophenyl)cyclopropyl)carbamate    (182);-   2-amino-N-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)acetamide    (183); or-   ((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(1-(4-fluorophenyl)cyclopropyl)amino)methyl    dihydrogen phosphate (184); and    -   pharmaceutically acceptable salts, co-crystals, tautomers,        stereoisomers, solvates, hydrates, polymorphs, isotopically        enriched derivatives, and prodrugs thereof.

In one aspect, the compound of Formula I is that wherein the compoundinhibits (or is identified to inhibit) histone deacetylase 6 (HDAC6).

The compounds herein include those wherein the compound is identified asattaining affinity, at least in part, for a metalloenzyme by formationof one or more of the following types of chemical interactions or bondsto a metal: sigma bonds, covalent bonds, coordinate-covalent bonds,ionic bonds, pi bonds, delta bonds, or backbonding interactions. Thecompounds can also attain affinity through weaker interactions with themetal such as van der Waals interactions, pi cation interactions,pi-anion interactions, dipole-dipole interactions, ion-dipoleinteractions. In one aspect, the compound is identified as having abonding interaction with the metal via the pyrimidine moiety.

Methods for assessing metal-ligand binding interactions are known in theart as exemplified in references including, for example, “Principles ofBioinorganic Chemistry” by Lippard and Berg, University Science Books,(1994); “Mechanisms of Inorganic Reactions” by Basolo and Pearson JohnWiley & Sons Inc; 2nd edition (September 1967); “Biological InorganicChemistry” by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine,University Science Books (2007); Xue et al. “Nature Chemical Biology”,vol. 4, no. 2, 107-109 (2008).

In another aspect, provided are pharmaceutical compositions comprisingthe compound of any of the formula herein (e.g., Formula I) and apharmaceutically acceptable carrier. In certain embodiments, thepharmaceutical composition comprises an additional therapeutic agent. Incertain embodiments, the additional therapeutic agent is an anti-canceragent (e.g., platinum-based chemotherapeutic agents, vinca alkaloids,Akt inhibitors, alkylating agents, androgen receptor antagonists,anti-estrogens, Bcl-2 inhibitors, BRAF kinase inhibitors, BTKinhibitors, CAR-T Cells, anti-CD38 antibodies, CDK inhibitors,anti-CTLA-4 antibodies, ERK/MAPK inhibitors, farnesyltransferaseinhibitors, IL-6 inhibitors, immunomodulatory agents, immuno-oncologyagents, JAK2/FLT3 inhibitors, kinesin spindle protein inhibitors, MEKinhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, PI3Kinhibitors, proteasome inhibitors, radiation (sensitizer), radioisotopes(sensitizer), synthetic retinoids (AM80), taxanes, tyrosine kinaseinhibitors, VDR agonists, VEGF inhibitors, or oncolytic viruses). Incertain embodiments, the pharmaceutical composition comprises two ormore additional therapeutic agents selected from those listed above.

In another aspect, provided are methods of inhibiting metalloenzymeactivity comprising contacting a compound of any of the formula herein(e.g., Formula I) with a metalloenzyme. In certain embodiments, thecontacting is in vivo. In certain embodiments, the contacting is invitro. In certain embodiments, the metalloenzyme comprises a metal atomthat is iron, zinc, heme iron, manganese, magnesium, iron sulfidecluster, nickel, molybdenum, or copper. In certain embodiments, themetalloenzyme is a histone deacetylase (HDAC). In certain embodiments,the metalloenzyme is HDAC6.

In another aspect, provided are methods of modulating metalloenzymeactivity in a subject, comprising contacting the subject with a compoundof any of the formula herein (e.g., Formula I), in an amount and underconditions sufficient to modulate metalloenzyme activity.

In another aspect, provided are methods of treating a subject sufferingfrom or susceptible to a disorder or disease, wherein the subject hasbeen identified as in need of treatment for the disorder or disease,comprising administering to said subject in need thereof, an effectiveamount of a compound or pharmaceutical composition of any of the formulaherein (e.g., Formula I), such that said subject is treated for saiddisorder.

In another aspect the subject is an animal other than a human.

In another aspect, provided are methods of treating a subject sufferingfrom or susceptible to a metalloenzyme-related disorder or disease,comprising administering to the subject an effective amount of acompound or pharmaceutical composition of any of the formula herein(e.g., Formula I).

In another aspect, provided are methods of treating a subject sufferingfrom or susceptible to a metalloenzyme-related disorder or disease,wherein the subject has been identified as in need of treatment for ametalloenzyme-related disorder or disease, comprising administering tosaid subject in need thereof, an effective amount of a compound orpharmaceutical composition of any of the formula herein (e.g., FormulaI), such that said subject is treated for said disorder.

In another aspect, provided are methods of treating a subject sufferingfrom or susceptible to a metalloenzyme-mediated disorder or disease,wherein the subject has been identified as in need of treatment for ametalloenzyme-mediated disorder or disease, comprising administering tosaid subject in need thereof, an effective amount of a compound orpharmaceutical composition of any of the formula herein (e.g., FormulaI), such that metalloenzyme activity in said subject is modulated (e.g.,down regulated, inhibited).

The methods herein include those wherein the disease or disorder ismediated by a histone deacetylase (e.g., HDAC6).

The methods herein include those wherein the disease or disorder iscancer, a proliferative disease, a neurodegenerative disease, pain, anautoimmune or inflammatory disorder, an infection, a metabolic disorder,an hematologic disorder, or a cardiovascular disease, or a combinationthereof.

The methods herein include those wherein the disease or disorder iscancer or a proliferative disease, wherein the cancer or proliferativedisease includes a carcinoma, a sarcoma, a leukemia, a blastoma, alymphoma, a myeloma, a melanoma, or a combination thereof.

The methods herein include those wherein the disease or disorder ismultiple myeloma, melanoma, breast cancer, pancreatic cancer, ovariancancer, prostate cancer, hepatocellular cancer, renal cancer, leukemia,T-cell lymphoma, cardiac cancer, bone cancer, glioblastoma,neuroblastoma, oral squamous cell carcinoma, urothelial cancer, lungcancer, cervical cancer, rectal cancer, liver cancer, pancreatic cancer,brain cancer, kidney cancer, stomach cancer, skin cancer, colon cancer,head and neck squamous cell carcinoma, Burkitt's Lymphoma, esophagealcancer, Hodgkin's lymphoma, bladder cancer, gastric cancer, or acombination thereof.

The methods herein include those wherein the disease or disorder isrheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, inflammatory boweldisease, graft versus host disease, transplant rejection, fibroticdisease, Crohn's Disease, type-1 diabetes, eczema, psoriasis, sepsis,airway hyperresponsiveness, ulcerative colitis, or a combinationthereof.

The methods herein include those wherein the disease or disorder isperipheral neuropathy, chemotherapy induced peripheral neuropathy,diabetic peripheral neuropathy, neuropathy, neuralgia, trigeminalneuralgia, postherpetic neuralgia, autoimmune peripheral neuropathy,Leber's hereditary optic neuropathy, POEMS syndrome, Cattleman disease,pain due to tumor infiltration, HIV related peripheral neuropathy,post-amputation phantom pain syndrome, Charcot-Marie Tooth disease,medication induced peripheral neuropathy, or a combination thereof.

The methods herein include those wherein the disease or disorder isepilepsy, attention deficit disorder, depression, anxiety, Alzheimer'sdisease, Parkinson's Disease, Huntington's Disease, amyotrophic lateralsclerosis, spinal muscular atrophy, essential tremor, central nervoussystem trauma, multiple sclerosis, Charcot-Marie-Tooth (MCT), cerebralischemia, stroke, Gulf War Illness, or a combination thereof.

The methods herein include those wherein the disease or disorder is aninfection caused by virus, fungus, or bacteria, or a combinationthereof.

The methods herein include those wherein the disease or disorder ismetabolic syndrome, diabetes, obesity, high blood pressure, heartfailure, cyst growth in autosomal dominant polycystic kidney disease(ADPKD), or a combination thereof.

The methods herein include those wherein the disease or disorder iscardiovascular stress, pressure overload, chronic ischemia,infarction-reperfusion injury, hypertension, atherosclerosis, peripheralartery disease, heart failure, hypertrophy, angina, arrhythmias,hypercholesterolemia, atherosclerosis, or stroke, or a combinationthereof.

Methods delineated herein include those wherein the subject isidentified as in need of a particular stated treatment. Identifying asubject in need of such treatment can be in the judgment of a subject ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

DETAILED DESCRIPTION Definitions

In order that the invention may be more readily understood, certainterms are first defined here for convenience.

As used herein, the term “treating” a disorder encompasses preventing,ameliorating, mitigating and/or managing the disorder and/or conditionsthat may cause the disorder. The terms “treating” and “treatment” referto a method of alleviating or abating a disease and/or its attendantsymptoms. In accordance with the present disclosure “treating” includespreventing, blocking, inhibiting, attenuating, protecting against,modulating, reversing the effects of and reducing the occurrence ofe.g., the harmful effects of a disorder.

As used herein, “inhibiting” encompasses preventing, reducing andhalting progression. Note that “enzyme inhibition” (e.g., metalloenzymeinhibition) is distinguished and described below.

The term “modulate” refers to increases or decreases in the activity ofan enzyme in response to exposure to a compound of the presentdisclosure.

The terms “isolated,” “purified,” or “biologically pure” refer tomaterial that is substantially or essentially free from components thatnormally accompany it as found in its native state. Purity andhomogeneity are typically determined using analytical chemistrytechniques such as polyacrylamide gel electrophoresis or highperformance liquid chromatography. Particularly, in embodiments thecompound is at least 85% pure, more preferably at least 90% pure, morepreferably at least 95% pure, and most preferably at least 99% pure.

The term “administration” or “administering” includes routes ofintroducing the compound(s) to a subject to perform their intendedfunction. Examples of routes of administration which can be used includeinjection (subcutaneous, intravenous, parenterally, intraperitoneally,intrathecal), topical, oral, inhalation, rectal and transdermal.

The term “effective amount” includes an amount effective, at dosages andfor periods of time necessary, to achieve the desired result. Aneffective amount of compound may vary according to factors such as thedisease state, age, and weight of the subject, and the ability of thecompound to elicit a desired response in the subject. Dosage regimensmay be adjusted to provide the optimum therapeutic response. Aneffective amount is also one in which any toxic or detrimental effects(e.g., side effects) of the inhibitor compound are outweighed by thetherapeutically beneficial effects.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound(s), drug or other material,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

A therapeutically effective amount of compound (i.e., an effectivedosage) may range from about 0.005 μg/kg to about 200 mg/kg, preferablyabout 0.01 mg/kg to about 200 mg/kg, more preferably about 0.015 mg/kgto about 30 mg/kg of body weight. In other embodiments, thetherapeutically effect amount may range from about 1.0 pM to about 10μM. The skilled artisan will appreciate that certain factors mayinfluence the dosage required to effectively treat a subject, includingbut not limited to the severity of the disease or disorder, previoustreatments, the general health and/or age of the subject, and otherdiseases present. Moreover, treatment of a subject with atherapeutically effective amount of a compound can include a singletreatment or, preferably, can include a series of treatments. In oneexample, a subject is treated with a compound in the range of betweenabout 0.005 μg/kg to about 200 mg/kg of body weight, one time per dayfor between about 1 to 10 weeks, preferably between 2 to 8 weeks, morepreferably between about 3 to 7 weeks, and even more preferably forabout 4, 5, or 6 weeks. In another example, a subject may be treateddaily for several years in the setting of a chronic condition orillness. It will also be appreciated that the effective dosage of acompound used for treatment may increase or decrease over the course ofa particular treatment.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not mirror images of oneanother.

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate.”

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

The term “prodrug” includes compounds with moieties which can bemetabolized in vivo. Generally, the prodrugs are metabolized in vivo byesterases or by other mechanisms to active drugs. Examples of prodrugsand their uses are well known in the art (See, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugs can beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form or hydroxyl with a suitable esterifying agent. Hydroxyl groupscan be converted into esters via treatment with a carboxylic acid.Examples of prodrug moieties include substituted and unsubstituted,branched or unbranched lower alkyl ester moieties, (e.g., propionoicacid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkylesters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters(e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g.,pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkylesters (e.g., benzyl ester), substituted (e.g., with methyl, halo, ormethoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionoic acid esters and acyl esters. Prodrugswhich are converted to active forms through other mechanisms in vivo arealso included. In aspects, the compounds of the present disclosure areprodrugs of any of the formulae herein.

The term “subject” refers to animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In certain embodiments, thesubject is a human.

The terms “a,” “an,” and “the” refer to “one or more” when used in thisapplication, including the claims. Thus, for example, reference to “asample” includes a plurality of samples, unless the context clearly isto the contrary (e.g., a plurality of samples), and so forth.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise.

As used herein, the term “about,” when referring to a value is meant toencompass variations of, in some embodiments ±20%, in some embodiments±10%, in some embodiments ±5%, in some embodiments ±1%, in someembodiments ±0.5%, and in some embodiments ±0.1% from the specifiedamount, as such variations are appropriate to perform the disclosedmethods or employ the disclosed compositions.

Use of the word “inhibitor” herein is meant to mean a molecule thatexhibits activity for inhibiting a metalloenzyme. By “inhibit” herein ismeant to decrease the activity of metalloenzyme, as compared to theactivity of metalloenzyme in the absence of the inhibitor. In someembodiments, the term “inhibit” means a decrease in metalloenzymeactivity of at least about 5%, at least about 10%, at least about 20%,at least about 25%, at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, or at least about95%. In other embodiments, inhibit means a decrease in metalloenzymeactivity of about 5% to about 25%, about 25% to about 50%, about 50% toabout 75%, or about 75% to 100%. In some embodiments, inhibit means adecrease in metalloenzyme activity of about 95% to 100%, e.g., adecrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreasescan be measured using a variety of techniques that would be recognizableby one of skill in the art. Particular assays for measuring individualactivity are described below.

Furthermore, the compounds of the present disclosure include olefinshaving either geometry: “Z” refers to what is referred to as a “cis”(same side) configuration whereas “E” refers to what is referred to as a“trans” (opposite side) configuration. With respect to the nomenclatureof a chiral center, the terms “d” and “1” configuration are as definedby the IUPAC Recommendations. As to the use of the terms, diastereomer,racemate, epimer and enantiomer, these will be used in their normalcontext to describe the stereochemistry of preparations.

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 12 carbon atoms. The term“lower alkyl” refers to a C1-C6 alkyl chain. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.Alkyl groups may be optionally substituted with one or moresubstituents.

The term “haloalkyl” refers to an alkyl group that is substituted by oneor more halo substituents. Examples of haloalkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl,chloromethyl, and 2,2,2-trifluoroethyl.

The term “alkenyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing 2 to 12 carbon atomsand at least one carbon-carbon double bond. Alkenyl groups may beoptionally substituted with one or more substituents.

The term “arylalkenyl” refers to an unsaturated hydrocarbon chain thatmay be a straight chain or branched chain, containing 2 to 12 carbonatoms and at least one carbon-carbon double bond wherein one or more ofthe sp² hybridized carbons of the alkenyl unit attaches to an arylmoiety. Alkenyl groups may be optionally substituted with one or moresubstituents.

The term “alkynyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbonatoms and at least one carbon-carbon triple bond. Alkynyl groups may beoptionally substituted with one or more substituents.

The term “arylalkynyl” refers to an unsaturated hydrocarbon chain thatmay be a straight chain or branched chain, containing 2 to 12 carbonatoms and at least one carbon-carbon triple bond wherein one or more ofthe sp hybridized carbons of the alkynyl unit attaches to an arylmoiety. Alkynyl groups may be optionally substituted with one or moresubstituents.

The sp² or sp carbons of an alkenyl group and an alkynyl group,respectively, may optionally be the point of attachment of the alkenylor alkynyl groups.

The term “alkoxy” refers to an —O-alkyl substituent.

As used herein, the term “halogen”, “hal” or “halo” means —F, —Cl, —Bror —I.

The term “alkylthio” refers to an —S-alkyl substituent.

The term “alkoxyalkyl” refers to an -alkyl-O-alkyl substituent.

The term “haloalkoxy” refers to an —O-alkyl that is substituted by oneor more halo substituents. Examples of haloalkoxy groups includetrifluoromethoxy, and 2,2,2-trifluoroethoxy.

The term “haloalkoxyalkyl” refers to an -alkyl-O-alkyl′ where the alkyl′is substituted by one or more halo substituents.

The term “haloalkylaminocarbonyl” refers to a —C(O)-amino-alkyl wherethe alkyl is substituted by one or more halo substituents.

The term “haloalkylthio” refers to an —S-alkyl that is substituted byone or more halo substituents. Examples of haloalkylthio groups includetrifluoromethylthio, and 2,2,2-trifluoroethylthio.

The term “haloalkylcarbonyl” refers to an —C(O)-alkyl that issubstituted by one or more halo substituents. An example of ahaloalkylcarbonyl group includes trifluoroacetyl.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one saturated ring orhaving at least one non-aromatic ring, wherein the non-aromatic ring mayhave some degree of unsaturation. Cycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a cycloalkyl group may be substituted by asubstituent.

Representative examples of cycloalkyl group include cyclopropyl,cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl,cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

The term “cycloalkoxy” refers to an —O-cycloalkyl substituent.

The term “cycloalkoxyalkyl” refers to an -alkyl-O-cycloalkylsubstituent.

The term “cycloalkylalkoxy” refers to an —O-alkyl-cycloalkylsubstituent.

The term “cycloalkylaminocarbonyl” refers to an —C(O)—NH-cycloalkylsubstituent.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term “aryloxy” refers to an —O-aryl substituent.

The term “arylalkoxy” refers to an —O-alkyl-aryl substituent.

The term “arylalkylthio” refers to an —S-alkyl-aryl substituent.

The term “arylthioalkyl” refers to an -alkyl-S -aryl substituent.

The term “arylalkylaminocarbonyl” refers to a —C(O)-amino-alkyl-arylsubstituent.

The term “arylalkylsulfonyl” refers to an —S(O)₂-alkyl-aryl substituent.

The term “arylalkylsulfinyl” refers to an —S(O)-alkyl-aryl substituent.

The term “aryloxyalkyl” refers to an -alkyl-O-aryl substituent.

The term “alkylaryl” refers to an -aryl-alkyl substituent.

The term “arylalkyl” refers to an -alkyl-aryl substituent.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andthe remainder ring atoms being carbon (with appropriate hydrogen atomsunless otherwise indicated). Heteroaryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heteroaryl group may be substituted by asubstituent. Examples of heteroaryl groups include pyridyl, furanyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl,isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and thelike.

The term “heteroarylalkyl” refers to an -alkyl-heteroaryl substituent.

The term “heteroaryloxy” refers to an —O-heteroaryl substituent.

The term “heteroarylalkoxy” refers to an —O-alkyl-heteroarylsubstituent.

The term “heteroaryloxyalkyl” refers to an -alkyl-O-heteroarylsubstituent.

The term “nitrogen-containing heteroaryl” refers to a heteroaryl grouphaving 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogenheteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

The term “heterocycloalkyl” refers to a nonaromatic 3-8 memberedmonocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, S, B, P or Si, wherein the nonaromatic ring system iscompletely saturated. Heterocycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heterocycloalkyl group may besubstituted by a substituent. Representative heterocycloalkyl groupsinclude piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl,thiirenyl, and the like.

The term “heterocycloalkylalkyl” refers to an -alkyl-heterocycloalkylsubstituent.

The term “alkylamino” refers to an amino substituent which is furthersubstituted with one or two alkyl groups. The term “aminoalkyl” refersto an alkyl substituent which is further substituted with one or moreamino groups. The term “hydroxyalkyl” or “hydroxylalkyl” refers to analkyl substituent which is further substituted with one or more hydroxylgroups. The alkyl or aryl portion of alkylamino, aminoalkyl,mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl,sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionallysubstituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Alkylating agents are any reagent that is capable of effecting thealkylation of the functional group at issue (e.g., oxygen atom of analcohol, nitrogen atom of an amino group). Alkylating agents are knownin the art, including in the references cited herein, and include alkylhalides (e.g., methyl iodide, benzyl bromide or chloride), alkylsulfates (e.g., methyl sulfate), or other alkyl group-leaving groupcombinations known in the art. Leaving groups are any stable speciesthat can detach from a molecule during a reaction (e.g., eliminationreaction, substitution reaction) and are known in the art, including inthe references cited herein, and include halides (e.g., I—, Cl—, Br—,F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc,—OC(O)CF₃), sulfonates (e.g., mesyl, tosyl), acetamides (e.g.,—NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g.,—OP(O)(OEt)₂), water or alcohols (protic conditions), and the like.

In certain embodiments, substituents on any group (such as, for example,alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, heterocycloalkyl) can be at any atom of that group, whereinany group that can be substituted (such as, for example, alkyl, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,heterocycloalkyl) can be optionally substituted with one or moresubstituents (which may be the same or different), each replacing ahydrogen atom. Examples of suitable substituents include, but are notlimited to alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano,nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl,alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido,carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl,sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N′-aryl,N″-hydroxyamidinyl. In certain embodiments, substituents on any groupinclude alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro,alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, thiocarbonyl, thio, mercapto, mercaptoalkyl,arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino,alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino,diarylamino, alkylcarbonyl, or arylamino-substituted aryl;arylalkylamino, aralkylaminocarbonyl, or amido. In certain embodiments,substituents on any group include alkyl, halogen, haloalkyl, cyano,nitro, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, formyl, alkylcarbonyl,alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino,aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, oralkylamino.

Compounds of the present disclosure can be made by means known in theart of organic synthesis. Methods for optimizing reaction conditions, ifnecessary minimizing competing by-products, are known in the art.Reaction optimization and scale-up may advantageously utilize high-speedparallel synthesis equipment and computer-controlled microreactors (e.g.Design And Optimization in Organic Synthesis, 2^(nd) Edition, Carlson R,Ed, 2005; Elsevier Science Ltd.; Jähnisch, K et al, Angew. Chem. Int.Ed. Engl. 2004 43: 406; and references therein). Additional reactionschemes and protocols may be determined by the skilled artesian by useof commercially available structure-searchable database software, forinstance, SciFinder® (CAS division of the American Chemical Society) andCrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searchingusing an internet search engine such as Google® or keyword databasessuch as the US Patent and Trademark Office text database.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art, including in the schemes and examples herein.Additionally, the various synthetic steps may be performed in analternate sequence or order to give the desired compounds. In addition,the solvents, temperatures, reaction durations, etc. delineated hereinare for purposes of illustration only and one of ordinary skill in theart will recognize that variation of the reaction conditions can producethe desired compounds of the present disclosure.

The compounds herein may also contain linkages (e.g., carbon-carbonbonds) wherein bond rotation is restricted about that particularlinkage, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded in the present disclosure. The compounds herein may also berepresented in multiple tautomeric forms, in such instances, the presentdisclosure expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented. All such isomeric forms of such compounds herein areexpressly included in the present disclosure. All crystal forms andpolymorphs of the compounds described herein are expressly included inthe present disclosure. Also embodied are extracts and fractionscomprising compounds of the present disclosure. The term isomers isintended to include diastereoisomers, enantiomers, regioisomers,structural isomers, rotational isomers, tautomers, and the like. Forcompounds which contain one or more stereogenic centers, e.g., chiralcompounds, the methods of the present disclosure may be carried out withan enantiomerically enriched compound, a racemate, or a mixture ofdiastereomers.

Preferred enantiomerically enriched compounds have an enantiomericexcess of 50% or more, more preferably the compound has an enantiomericexcess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In preferredembodiments, only one enantiomer or diastereomer of a chiral compound ofthe present disclosure is administered to cells or a subject.

Reference to compounds of Formula (I) herein include those compounds ofFormulae I-a to I-i.

Methods of Treatment

In one aspect, provided are methods of treating a subject suffering fromor susceptible to a disorder or disease, comprising administering to thesubject an effective amount of a compound or pharmaceutical compositionof any of the formula herein (e.g., Formula I).

In other aspects, provided are methods of treating a subject sufferingfrom or susceptible to a disorder or disease, wherein the subject hasbeen identified as in need of treatment for a metalloenzyme-mediateddisorder or disease, comprising administering to said subject in needthereof, an effective amount of a compound or pharmaceutical compositionof any of the formula herein (e.g., Formula I), such that said subjectis treated for said disorder.

In one aspect, provided are methods of modulating the metalloenzymeactivity of a cell in a subject, comprising contacting the subject witha compound of any of the formula herein (e.g., Formula I), in an amountand under conditions sufficient to modulate metalloenzyme activity.

In one embodiment, the modulation is inhibition.

In another aspect, provided are methods of treating a subject sufferingfrom or susceptible to a metalloenzyme-mediated disorder or disease,comprising administering to the subject an effective amount of acompound or pharmaceutical composition of any of the formula herein(e.g., Formula I).

In other aspects, provided are methods of treating a subject sufferingfrom or susceptible to a metalloenzyme-mediated disorder or disease,wherein the subject has been identified as in need of treatment for ametalloenzyme-mediated disorder or disease, comprising administering tosaid subject in need thereof, an effective amount of a compound orpharmaceutical composition of any of the formula herein (e.g., FormulaI), such that said subject is treated for said disorder.

In certain embodiments, provided are methods of treating a disease,disorder or symptom thereof, wherein the disorder is cancer, aproliferative disease, a neurodegenerative disease, pain, an autoimmuneor inflammatory disorder, an infection, a metabolic disorder, anhematologic disorder, or a cardiovascular disease.

In certain embodiments, the disorder or disease is cancer or aproliferative disease. In certain embodiments, the cancer orproliferative disease includes a carcinoma, a sarcoma, a leukemia, ablastoma, a lymphoma, a myeloma, or a melanoma, or a combinationthereof. In certain embodiments, the disorder or disease is multiplemyeloma, melanoma, breast cancer, pancreatic cancer, ovarian cancer,prostate cancer, hepatocellular cancer, renal cancer, leukemia, T-celllymphoma, cardiac cancer, bone cancer, glioblastoma, neuroblastoma, oralsquamous cell carcinoma, urothelial cancer, lung cancer, cervicalcancer, rectal cancer, liver cancer, pancreatic cancer, brain cancer,kidney cancer, stomach cancer, skin cancer, colon cancer, head and necksquamous cell carcinoma, Burkitt's Lymphoma, esophageal cancer,Hodgkin's lymphoma, bladder cancer, or gastric cancer, or a combinationthereof.

In certain embodiments, the disorder or disease is rheumatoid arthritis,spondylitis arthritis, psoriatic arthritis, multiple sclerosis, systemiclupus erythematosus, inflammatory bowel disease, graft versus hostdisease, transplant rejection, fibrotic disease, Crohn's Disease, type-1diabetes, eczema, psoriasis, sepsis, airway hyperresponsiveness,ulcerative colitis, or a combination thereof.

In certain embodiments, the disorder or disease is peripheralneuropathy, chemotherapy induced peripheral neuropathy, diabeticperipheral neuropathy, neuropathy, neuralgia, trigeminal neuralgia,postherpetic neuralgia, autoimmune peripheral neuropathy, Leber'shereditary optic neuropathy, POEMS syndrome, Cattleman disease, pain dueto tumor infiltration, HIV related peripheral neuropathy,post-amputation phantom pain syndrome, Charcot-Marie Tooth disease,medication induced peripheral neuropathy, or a combination thereof.

In certain embodiments, the disorder or disease is peripheralneuropathy, including drug induced peripheral neuropathy (e.g.,chemotherapy induced peripheral neuropathy). In certain embodiments, thedisorder or disease is peripheral neuropathy induced by treatment withan anti-cancer agent (e.g., alkylating agents, CAR-T Cells, anti-CD38antibodies, anti-CTLA-4 antibodies, epothilones, immunomodulatoryagents, immuno-oncology agents, anti-PD-1 antibodies, anti-PD-L1antibodies, proteasome inhibitors, taxanes, platinum-basedchemotherapeutic agents, and vinca alkaloids). In certain embodiments,the disorder or disease is peripheral neuropathy induced by treatmentwith arsenic trioxide, bortezomib, cabazitaxel, carboplatin,carfilzomib, cisplatin, carboplatin, oxaliplatin, cyclophosphamide,darzalex, docetaxel, elotuzumab, eribulin, fluorouracil (5-FU),gefitinib, gemcitabine hydrochloride, indatuximab, ixazomib, ravtansine,ipilimumab, ixabepilone, lenalidomide, nab-paclitaxel, nivolumab,oxaliplatin, paclitaxel, pomalidomide, temozolomide, thalidomide,vinblastine, vincristine, vindesine, or vinorelbine.

In certain embodiments, the disorder or disease is peripheral neuropathyinduced by treatment with a drug other than an anti-cancer agent (e.g.,cardiovascular agents, statins, antimicrobial agents,immunosuppressants, anti-alcohol drugs, anticonvulsants, TNF-αinhibitors, and nucleoside analog reverse transcriptase inhibitors(NRTIs)). In certain embodiments, the disorder or disease is peripheralneuropathy induced by treatment with atorvastatin, pitavastatin,lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin,amiodarone, chloramphenicol, chloroquine, dapsone, fluoroquinolones,hydralazine, etanercept, ethambutol, isoniazid, linezolid,metronidazole, nitrofurantoin, leflunomide, phenytoin, didanosine,stavudine, or zalcitabine.

In certain embodiments, the disorder or disease is cancer and peripheralneuropathy (e.g., chemotherapy induced peripheral neuropathy).

In certain embodiments, the disorder or disease is epilepsy, attentiondeficit disorder, depression, anxiety, Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma,multiple sclerosis, Charcot-Marie-Tooth (MCT), cerebral ischemia,stroke, Gulf War Illness, or a combination thereof.

In certain embodiments, the disorder or disease is an infection causedby virus, fungus, or bacteria, or a combination thereof.

In certain embodiments, the disorder or disease is metabolic syndrome,diabetes, obesity, high blood pressure, heart failure, cyst growth inautosomal dominant polycystic kidney disease (ADPKD), or a combinationthereof.

In certain embodiments, the disorder or disease is cardiovascularstress, pressure overload, chronic ischemia, infarction-reperfusioninjury, hypertension, atherosclerosis, peripheral artery disease, heartfailure, hypertrophy, angina, arrhythmias, hypercholesterolemia,atherosclerosis, or stroke, or a combination thereof.

In certain embodiments, the subject is a mammal, preferably a primate orhuman.

In another embodiment, provided are methods as described above, whereinthe effective amount of the compound of any of the formula herein (e.g.,Formula I) is as described above.

In another embodiment, provided are methods as described above, whereinthe compound of any of the formula herein (e.g., Formula I) isadministered intravenously, intramuscularly, subcutaneously,intracerebroventricularly, orally or topically.

In another embodiment, provided are methods as described herein whereinthe compound of any of the formula herein (e.g., Formula I) demonstratesselectivity for an activity range against a target enzyme (e.g., HDAC6IC₅₀<1.0 μM).

In certain embodiments, the compound of any of the formula herein (e.g.,Formula I) selectively inhibits HDAC6 over another protein. In someembodiments, the compound of any of the formula herein (e.g., Formula I)selectively inhibits HDAC6 over another HDAC. In some embodiments, thecompound of any of the formula herein (e.g., Formula I) selectivelyinhibits HDAC6 over a class I HDAC (e.g., HDAC1, HDAC2, HDAC3, HDAC8).In some embodiments, the compound of any of the formula herein (e.g.,Formula I) selectively inhibits HDAC6 over a class IIA HDAC (e.g.,HDAC4, HDAC5, HDAC7, HDAC9). In some embodiments, the compound of any ofthe formula herein (e.g., Formula I) selectively inhibits HDAC6 over aclass IIB HDAC (e.g., HDAC10). In some embodiments, the compound of anyof the formula herein (e.g., Formula I) selectively inhibits HDAC6 overa class III HDAC (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6,SIRT7). In some embodiments, the compound of any of the formula herein(e.g., Formula I) selectively inhibits HDAC6 over a class IV HDAC (e.g.,HDAC11). In some embodiments, the compound of any of the formula herein(e.g., Formula I) selectively inhibits HDAC6 over HDAC1, HDAC2, HDAC3,HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11. In certainembodiments, the selectivity is between about 2-fold and about 5-fold.In certain embodiments, the selectivity is between about 5-fold andabout 10-fold. In certain embodiments, the selectivity is between about10-fold and about 20-fold. In certain embodiments, the selectivity isbetween about 20-fold and about 50-fold. In certain embodiments, theselectivity is between about 50-fold and about 100-fold. In certainembodiments, the selectivity is between about 100-fold and about200-fold. In certain embodiments, the selectivity is between about200-fold and about 500-fold. In certain embodiments, the selectivity isbetween about 500-fold and about 1000-fold. In certain embodiments, theselectivity is at least about 1000-fold.

In other embodiments, provided are methods as described above, whereinthe compound of any of the formula herein (e.g., Formula I) isadministered alone or in combination with one or more othertherapeutics. In a further embodiment, the additional therapeutic agentis an anti-cancer agent, antifungal agent, cardiovascular agent,anti-inflammatory agent, chemotherapeutic agent, an anti-angiogenesisagent, cytotoxic agent, an anti-proliferation agent, metabolic diseaseagent, ophthalmologic disease agent, central nervous system (CNS)disease agent, urologic disease agent, or gastrointestinal diseaseagent.

Another object of the present disclosure is the use of a compound asdescribed herein (e.g., a compound of Formula I) in the manufacture of amedicament for use in the treatment of a metalloenzyme-mediated disorderor disease. Another object of the present disclosure is the use of acompound as described herein (e.g., a compound of Formula I) for use inthe treatment of a metalloenzyme-mediated disorder or disease. Anotherobject of the present disclosure is the use of a compound as describedherein (e.g., a compound of Formula I) in the manufacture of anagricultural composition for use in the treatment or prevention of ametalloenzyme-mediated disorder or disease in agricultural or agrariansettings.

Pharmaceutical Compositions

In one aspect, provided are pharmaceutical compositions comprising thecompound of any of the formula herein (e.g., Formula I) and apharmaceutically acceptable carrier.

A compound or composition, as described herein, can be administered incombination with one or more additional therapeutic agents (e.g.,therapeutically and/or prophylactically active agents). The compounds orcompositions can be administered in combination with additionaltherapeutic agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a disease in a subject in needthereof, in preventing a disease in a subject in need thereof, and/or inreducing the risk to develop a disease in a subject in need thereof),improve bioavailability, improve safety, reduce drug resistance, reduceand/or modify metabolism, inhibit excretion, and/or modify distributionin a subject or cell. It will also be appreciated that the therapyemployed may achieve a desired effect for the same disorder, and/or itmay achieve different effects. In certain embodiments, a pharmaceuticalcomposition described herein including a compound described herein andan additional therapeutic agent to exhibit a synergistic effect that isabsent in a pharmaceutical composition including one of the compound andthe additional therapeutic agent, but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional therapeutic agents, whichmay be useful as, e.g., combination therapies. Therapeutic agentsinclude therapeutically active agents. Therapeutic agents also includeprophylactically active agents. Therapeutic agents include small organicmolecules such as drug compounds (e.g., compounds approved for human orveterinary use by the U.S. Food and Drug Administration as provided inthe Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional therapeutic agent is a therapeuticagent useful for treating and/or preventing a disease (e.g., cancer,proliferative disease, neurodegenerative disease, autoimmune orinflammatory disorder, infection, metabolic disorder, hematologicdisorder, cardiovascular disease). Each additional therapeutic agent maybe administered at a dose and/or on a time schedule determined for thattherapeutic agent. The additional therapeutic agents may also beadministered together with each other and/or with the compound orcomposition described herein in a single dose or administered separatelyin different doses. The particular combination to employ in a regimenwill take into account compatibility of the compound described hereinwith the additional therapeutic agent(s) and/or the desired therapeuticand/or prophylactic effect to be achieved. In general, it is expectedthat the additional therapeutic agent(s) in combination be utilized atlevels that do not exceed the levels at which they are utilizedindividually. In some embodiments, the levels utilized in combinationwill be lower than those utilized individually.

In certain embodiments, the additional therapeutic agent (e.g., as partof a pharmaceutical composition or a combination therapy) may induce anundesired side effect (e.g., peripheral neuropathy). The compound ofFormula I is useful for treatment of the undesired side effect whenadministered in combination with the additional therapeutic agent (e.g.,as part of a pharmaceutical composition or a combination therapy).

The additional therapeutic agents include, but are not limited to,anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents,anti-inflammatory agents, and immunosuppressants. In certainembodiments, the additional therapeutic agent is an immunotherapy. Incertain embodiments, the additional therapeutic agent is ananti-proliferative agent. In certain embodiments, the additionaltherapeutic agent is an anti-cancer agent. In certain embodiments, theanti-cancer agents include, but are not limited to, epigenetic ortranscriptional modulators (e.g., DNA methyltransferase inhibitors,histone deacetylase inhibitors (HDAC inhibitors), lysinemethyltransferase inhibitors), antimitotic drugs (e.g., taxanes andvinca alkaloids), cell signaling pathway inhibitors (e.g., tyrosineprotein kinase inhibitors), modulators of protein stability (e.g.,proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-transretinoic acids, anti-estrogens (e.g., tamoxifen, raloxifene, andmegestrol), LHRH agonists (e.g., goscrclin and leuprolide),anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies(e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, anddemethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g.,cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine,and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine(CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes(e.g. dacarbazine, temozolomide), platinum-based chemotherapeutic agents(e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g.vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g.paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-boundpaclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel(DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel(PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), thetumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to threemolecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to theerbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel,e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel,taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate),IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin,ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.,hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil(5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil,capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosinearabinoside, and fludarabine), purine analogs (e.g. mercaptopurine andThioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060),isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins(e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca2+ATPase inhibitors (e.g., thapsigargin),thalidomide, lenalidomide, pomalidomide, tyrosine kinase inhibitors(e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (VELCADE), ixazomib(NINLARO)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779),everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055(AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) andOSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin,pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine.

In certain embodiments, the additional therapeutic agent is animmunotherapy. In certain embodiments, the immunotherapy is useful inthe treatment of a cancer. Exemplary immunotherapies include, but arenot limited to, T-cell therapies, interferons, cytokines (e.g., tumornecrosis factor, interferon α, interferon γ), vaccines, hematopoieticgrowth factors, monoclonal serotherapy, immunostimulants and/orimmunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growthfactors (e.g., GM-CSF) and antibodies. In certain embodiments, theimmunotherapy is a T-cell therapy. In certain embodiments, the T-celltherapy is chimeric antigen receptor T cells (CAR-T). In certainembodiments, the immunotherapy is an antibody. In certain embodiments,the antibody is an anti-PD-1 antibody, an anti-PD-L1 antibody, ananti-CTLA-4 antibody, an anti-TIM3 antibody, an anti-OX40 antibody, ananti-GITR antibody, an anti-LAG-3 antibody, an anti-CD137 antibody, ananti-CD27 antibody, an anti-CD28 antibody, an anti-CD28H antibody, ananti-CD30 antibody, an anti-CD39 antibody, an anti-CD40 antibody, ananti-CD47 antibody, an anti-CD48 antibody, an anti-CD70 antibody, ananti-CD73 antibody, an anti-CD96 antibody, an anti-CD160 antibody, ananti-CD200 antibody, an anti-CD244 antibody, an anti-ICOS antibody, ananti-TNFRSF25 antibody, an anti-TMIGD2 antibody, an anti-DNAM1 antibody,an anti-BTLA antibody, an anti-LIGHT antibody, an anti-TIGIT antibody,an anti-VISTA antibody, an anti-HVEM antibody, an anti-Siglec antibody,an anti-GAL1 antibody, an anti-GAL3 antibody, an anti-GAL9 antibody, ananti-BTNL2 (butrophylins) antibody, an anti-B7-H3 antibody, ananti-B7-H4 antibody, an anti-B7-H5 antibody, an anti-B7-H6 antibody, ananti-KIR antibody, an anti-LIR antibody, an anti-ILT antibody, ananti-MICA antibody, an anti-MICB antibody, an anti-NKG2D antibody, ananti-NKG2A antibody, an anti-TGFP3 antibody, an anti-TGFP3R antibody, ananti-CXCR4 antibody, an anti-CXCL12 antibody, an anti-CCL2 antibody, ananti-IL-10 antibody, an anti-IL-13 antibody, an anti-IL-23 antibody, ananti-phosphatidylserine antibody, an anti-neuropilin antibody, ananti-GalCer antibody, an anti-HER2 antibody, an anti-VEGFA antibody, ananti-VEGFR antibody, an anti-EGFR antibody, or an anti-Tie2 antibody. Incertain embodiments, the antibody is pembrolizumab, nivolumab,pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab,avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525,AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566,urelumab, lirilumab, lulizumab, BMS-936559, BMS-936561, BMS-986004,BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, varilumab,ulocuplumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383,MEDI6469, MEDI9447, AMG228, AMG820, CC-90002, CDX-1127, CGEN15001T,CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092,CX-072, CX-2009, CP-870893, lucatumumab, dacetuzumab, Chi Lob 7/4,RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, MGA271, IMC-CS4,emactuzumab, trastuzumab, pertuzumab, obinutuzumab, cabiralizumab,margetuximab, enoblituzumab, mogamulizumab, panitumumab, carlumab,bevacizumab, rituximab, or cetuximab.

In certain embodiments, the compounds or pharmaceutical compositionsdescribed herein can be administered in combination with an anti-cancertherapy including, but not limited to, surgery, radiation therapy, andtransplantation (e.g., stem cell transplantation, bone marrowtransplantation).

In certain embodiments, the additional therapeutic agent is selectedfrom the group consisting of platinum-based chemotherapeutic agents,vinca alkaloids, Akt inhibitors, alkylating agents, androgen receptorantagonists, anti-estrogens, Bcl-2 inhibitors, BRAF kinase inhibitors,BTK inhibitors, CAR-T Cells, anti-CD38 antibodies, CDK inhibitors,anti-CTLA-4 antibodies, ERK/MAPK inhibitors, farnesyltransferaseinhibitors, IL-6 inhibitors, immunomodulatory agents, immuno-oncologyagents, JAK2/FLT3 inhibitors, kinesin spindle protein inhibitors, MEKinhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, PI3Kinhibitors, proteasome inhibitors, radiation (sensitizer), radioisotopes(sensitizer), synthetic retinoids (AM80), taxanes, tyrosine kinaseinhibitors, VDR agonists, VEGF inhibitors, oncolytic viruses, and acombination thereof.

In certain embodiments, the additional therapeutic agent is selectedfrom the group consisting of all trans tetinoic acid (ATRA), arsenictrioxide, berberine, bevacizumab, bortezomib, cabazitaxel, carfilzomib,cisplatin, carboplatin, oxaliplatin, clarithromycin, cyclophosphamide,cytarabine, darzalex, dexamethasone, docetaxel, elotuzumab,enzalutamide, epirubicin, fluorouracil (5-FU), gefitinib, gemcitabinehydrochloride, ibrutinib, idelalisib, indatuximab, ixazomib, ravtansine,ipilimumab, lenalidomide, lonafarnib, methotrexate, nab-paclitaxel,nivolumab, paclitaxel, pacritinib, pomalidomide, sorafenib,temozolomide, thalidomide, vemurafenib, vinblastine, vindesine,vinorelbine, and vincristine.

In certain embodiments, the additional therapeutic agent is selectedfrom the group consisting of cardiovascular agents, statins,antimicrobial agents, immunosuppressants, anti-alcohol drugs,anticonvulsants, TNF-α inhibitors, and nucleoside analog reversetranscriptase inhibitors (NRTIs). In certain embodiments, the additionaltherapeutic agent is atorvastatin, pitavastatin, lovastatin,simvastatin, pravastatin, fluvastatin, rosuvastatin, amiodarone,chloramphenicol, chloroquine, dapsone, fluoroquinolones, hydralazine,etanercept, ethambutol, isoniazid, linezolid, metronidazole,nitrofurantoin, leflunomide, phenytoin, didanosine, stavudine, orzalcitabine.

In one aspect, provided are kits comprising an effective amount of acompound of Formula I, in unit dosage form, together with instructionsfor administering the compound to a subject suffering from orsusceptible to a metalloenzyme-mediated disease or disorder, includingcancer, proliferative disease, neurodegenerative disease, autoimmune orinflammatory disorder, infection, metabolic disorder, hematologicdisorder, and cardiovascular disease. In other embodiments the disease,disorder or symptom thereof is a carcinoma, a leukemia, a blastoma, alymphoma, a myeloma, or a melanoma. In other embodiments the disease,disorder or symptom thereof is multiple myeloma, melanoma, breastcancer, pancreatic cancer, ovarian cancer, prostate cancer,hepatocellular cancer, renal cancer, leukemia, T-cell lymphoma, bonecancer, glioblastoma, neuroblastoma, oral squamous cell carcinoma,urothelial cancer, lung cancer, cervical cancer, colon cancer, head andneck squamous cell carcinoma, Burkitt's Lymphoma, esophageal cancer,Hodgkin's lymphoma, bladder cancer, or gastric cancer. In otherembodiments the disease, disorder or symptom thereof is rheumatoidarthritis, spondylitis arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, inflammatory bowel disease,graft versus host disease, transplant rejection, fibrotic disease,Crohn's Disease, type-1 diabetes, eczema, psoriasis, sepsis, airwayhyperresponsiveness, or ulcerative colitis. In other embodiments thedisease, disorder or symptom thereof is epilepsy, attention deficitdisorder, Alzheimer's disease, Parkinson's Disease, Huntington'sDisease, amyotrophic lateral sclerosis, spinal muscular atrophy,essential tremor, central nervous system trauma, multiple sclerosis,Charcot-Marie-Tooth (MCT), peripheral neuropathy, or cerebral ischemia.In other embodiments the disease, disorder or symptom thereof is aninfection caused by virus, fungus, or bacteria. In other embodiments thedisease, disorder or symptom thereof is metabolic syndrome, diabetes,obesity, high blood pressure, heart failure, or cyst growth in autosomaldominant polycystic kidney disease (ADPKD). In other embodiments thedisease, disorder or symptom thereof is cardiovascular stress, pressureoverload, chronic ischemia, infarction-reperfusion injury, hypertension,atherosclerosis, peripheral artery disease, heart failure, hypertrophy,angina, arrhythmias, hypercholesterolemia, atherosclerosis, or stroke.

The term “pharmaceutically acceptable salts” or “pharmaceuticallyacceptable carrier” is meant to include salts of the active compoundswhich are prepared with relatively nontoxic acids or bases, depending onthe particular substituents found on the compounds described herein.When compounds of the present disclosure contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When compounds of the present disclosure containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present disclosure containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present disclosure.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

The present disclosure also provides a pharmaceutical composition,comprising an effective amount a compound described herein and apharmaceutically acceptable carrier. In an embodiment, a compound of anyof the formula herein (e.g., Formula I) is administered to a subjectusing a pharmaceutically-acceptable formulation, e.g., apharmaceutically-acceptable formulation that provides sustained deliveryof the compound to a subject for at least 12 hours, 24 hours, 36 hours,48 hours, one week, two weeks, three weeks, or four weeks after thepharmaceutically-acceptable formulation is administered to the subject.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the disclosure may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic(or unacceptably toxic) to the patient.

In use, at least one compound according to the present disclosure isadministered in a pharmaceutically effective amount to a subject in needthereof in a pharmaceutical carrier by intravenous, intramuscular,subcutaneous, or intracerebroventricular injection or by oraladministration or topical application. In accordance with the presentdisclosure, a compound of the disclosure may be administered alone or inconjunction with a second, different therapeutic. By “in conjunctionwith” is meant together, substantially simultaneously or sequentially.In one embodiment, a compound of the disclosure is administered acutely.The compound of the disclosure may therefore be administered for a shortcourse of treatment, such as for about 1 day to about 1 week. In anotherembodiment, the compound of the disclosure may be administered over alonger period of time to ameliorate chronic disorders, such as, forexample, for about one week to several months depending upon thecondition to be treated.

By “pharmaceutically effective amount” as used herein is meant an amountof a compound of the disclosure, high enough to significantly positivelymodify the condition to be treated but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. A pharmaceutically effective amount of a compound ofthe disclosure will vary with the particular goal to be achieved, theage and physical condition of the patient being treated, the severity ofthe underlying disease, the duration of treatment, the nature ofconcurrent therapy and the specific compound employed. For example, atherapeutically effective amount of a compound of the disclosureadministered to a child or a neonate will be reduced proportionately inaccordance with sound medical judgment. The effective amount of acompound of the disclosure will thus be the minimum amount which willprovide the desired effect.

A decided practical advantage of the present disclosure is that thecompound may be administered in a convenient manner such as byintravenous, intramuscular, subcutaneous, oral orintra-cerebroventricular injection routes or by topical application,such as in creams or gels. Depending on the route of administration, theactive ingredients which comprise a compound of the disclosure may berequired to be coated in a material to protect the compound from theaction of enzymes, acids and other natural conditions which mayinactivate the compound. In order to administer a compound of thedisclosure by other than parenteral administration, the compound can becoated by, or administered with, a material to prevent inactivation.

The compound may be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquidpolyethylene glycols, and mixtures thereof, and in oils.

Some examples of substances which can serve as pharmaceutical carriersare sugars, such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethycellulose, ethylcellulose and cellulose acetates; powderedtragancanth; malt; gelatin; talc; stearic acids; magnesium stearate;calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil,sesame oil, olive oil, corn oil and oil of theobroma; polyols such aspropylene glycol, glycerine, sorbitol, mannitol, and polyethyleneglycol; agar; alginic acids; pyrogen-free water; isotonic saline; andphosphate buffer solution; skim milk powder; as well as other non-toxiccompatible substances used in pharmaceutical formulations such asVitamin C, estrogen and echinacea, for example. Wetting agents andlubricants such as sodium lauryl sulfate, as well as coloring agents,flavoring agents, lubricants, excipients, tableting agents, stabilizers,anti-oxidants and preservatives, can also be present. Solubilizingagents, including for example, cremaphore and beta-cyclodextrins canalso used in the pharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds of thepresent disclosure (or prodrugs thereof) can be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions can be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically.

Pharmaceutical compositions of the present disclosure subject matter cantake a form suitable for virtually any mode of administration,including, for example, topical, ocular, oral, buccal, systemic, nasal,injection, transdermal, rectal, vaginal, and the like, or a formsuitable for administration by inhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) can beformulated as solutions, gels, ointments, creams, suspensions, and thelike.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions also can contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection canbe presented in unit dosage form (e.g., in ampules or in multidosecontainers) and can contain added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, and the like,before use. To this end, the active compound(s) can be dried by anyart-known technique, such as lyophilization, and reconstituted prior touse.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions can take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars or enteric coatings.

Liquid preparations for oral administration can take the form of, forexample, elixirs, solutions, syrups or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils); and preservatives (e.g., methylor propyl p-hydroxybenzoates or sorbic acid). The preparations also cancontain buffer salts, preservatives, flavoring, coloring and sweeteningagents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in a conventional manner.

For rectal and vaginal routes of administration, the active compound(s)can be formulated as solutions (for retention enemas), suppositories, orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

For ocular administration, the active compound(s) or prodrug(s) can beformulated as a solution, emulsion, suspension, and the like, suitablefor administration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. Nos. 6,261,547;6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222;5,403,841; 5,077,033; 4,882,150; and 4,738,851, each of which isincorporated herein by reference in its entirety.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient can be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, each of whichis incorporated herein by reference in its entirety.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) also can be employed.

The pharmaceutical compositions can, if desired, be presented in a packor dispenser device which can contain one or more unit dosage formscontaining the active compound(s). The pack can, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

The active compound(s) or prodrug(s) of the present disclosure, orcompositions thereof, will generally be used in an amount effective toachieve the intended result, for example in an amount effective to treator prevent the particular disease being treated. The compound(s) can beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient can still be afflicted with the underlying disorder. Therapeuticbenefit also includes halting or slowing the progression of the disease,regardless of whether improvement is realized.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously described diseases.A patient at risk of developing a disease can be a patient havingcharacteristics placing the patient in a designated group of at riskpatients, as defined by an appropriate medical professional or group. Apatient at risk may also be a patient that is commonly or routinely in asetting where development of the underlying disease that may be treatedby administration of a metalloenzyme inhibitor according to the presentdisclosure could occur. In other words, the at risk patient is one whois commonly or routinely exposed to the disease or illness causingconditions or may be acutely exposed for a limited time. Alternatively,prophylactic administration can be applied to avoid the onset ofsymptoms in a patient diagnosed with the underlying disorder.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, and the like. Determination of aneffective dosage is well within the capabilities of those skilled in theart.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay, such as the in vitro fungal MIC or MFC and other invitro assays described in the Examples section. Calculating dosages toachieve such circulating blood or serum concentrations taking intoaccount the bioavailability of the particular compound is well withinthe capabilities of skilled artisans. For guidance, see Fingl &Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein, which areincorporated herein by reference.

Initial dosages also can be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration, and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. In cases oflocal administration or selective uptake, such as local topicaladministration, the effective local concentration of active compound(s)cannot be related to plasma concentration. Skilled artisans will be ableto optimize effective local dosages without undue experimentation.

The compound(s) can be administered once per day, a few or several timesper day, or even multiple times per day, depending upon, among otherthings, the indication being treated and the judgment of the prescribingphysician.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The examples describedin this application are offered to illustrate the compounds,pharmaceutical compositions, and methods provided herein and are not tobe construed in any way as limiting their scope.

General Experimental Procedures

Definitions of variables in the structures in schemes herein arecommensurate with those of corresponding positions in the formulaedelineated herein. The example compounds listed in Table 2 werecharacterized by the HPLC and LCMS methods described in Table 1.

Common Abbreviations:

ACN acetonitrilebr broadd doubletDCM dichloromethanedd doublet of doubletsdba dibenzylideneacetoneDFAA difluoroacetic anhydrideDIPEA diisopropylethylamineDMF dimethylformamideDMSO dimethyl sulfoxidedppf 1,1′-ferrocenediyl-bis(diphenylphosphine)EtOAc ethyl acetateh hour(s)HRMS high resolution mass spectrometryHPLC high performance liquid chromatographyLCMS liquid chromatography and mass spectrometryMS mass spectrometryMW microwavem multipletMeOH methanolmin minutesmL milliliter(s)m/z mass to charge ratioNMP N-methyl-2-pyrrolidoneNMR nuclear magnetic resonanceppm parts per millionrt or RT room temperatures singlett tripletTFAA trifluoroacetic anhydrideTLC thin layer chromatography

Example 1N-(1-phenylcyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(1)

1-phenylcyclopropan-1-amine (B)

To a stirred solution of benzonitrile (A, 5.0 g, 48.54 mmol) in diethylether (50 mL), ethyl magnesium bromide (3M, 34.20 mL, 106.7 mmol) andtitanium isopropoxide (15.16 g, 53.39 mmol) were added at −70° C. andthe reaction was stirred at RT for 2 h. BF₃.OEt₂ (13.77 g, 97.08 mmol)was added at 0° C. and stirred at RT for 8 h. The progress of thereaction was monitored by thin layer chromatography (TLC). Aftercompletion of the reaction, the reaction mixture was quenched with NH₄Clsolution and basified with 10% NaOH solution, extracted with 10%(MeOH/DCM). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography 50%EtOAc/hexane to afford compound B (5.0 g, 38.7%) as a pale-yellowliquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.32 (m, 4H), 7.10 (m, 1H), 2.23 (s,2H), 0.98-0.90 (m, 2H), 0.93-0.82 (m, 2H).

5-bromo-N-(1-phenylcyclopropyl)pyrimidin-2-amine (D)

To a stirred solution of 2-bromo-5-chloropyrimidine (C, 5.0 g, 25.8mmol) and compound B (6.8 g, 51.6 mmol) in EtOH (50 mL), DIPEA (19 mL,103 mmol) was added and stirred at 90° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography 20%EtOAc/hexane to afford compound D (3.3 g, 44.6%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (br s, 1H), 8.32 (s, 2H), 7.22(t, J=7.6 Hz, 2H), 7.13-7.08 (m, 3H), 1.26-1.19 (m, 4H); LC-MS: m/z290.05 [M+H]⁺.

2-((1-phenylcyclopropyl)amino)pyrimidine-5-carbonitrile (E)

To a stirred solution of compound D (2.2 g, 7.58 mmol) in DMF (15 mL),Zn(CN)₂ (1.77 g, 15.1 mmol) was added and degassed under argonatmosphere for 20 min. To the resulting reaction mixture Pd(PPh₃)₄(0.86g, 0.75 g) was added and degassed for 15 min. The reaction mixture wasstirred at 100° C. for 16 h. After completion of the reaction, thereaction mixture was filtered through a pad of Celite, diluted withwater and extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatography30% EtOAc/hexane to afford E (1.2 g, 60%) as an off white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.69 (dd, J=4.4, 2.8 Hz, 2H), 7.24(t, J=7.6 Hz, 2H), 7.13-7.11 (m, 3H), 1.31-1.22 (m, 4H); LC-MS: m/z237.0 [M+H]⁺.

N-(1-phenylcyclopropyl)-5-(5H-tetrazol-5-yl)pyrimidin-2-amine (F)

To a stirred solution of compound E (300 mg, 1.27 mmol) in DMF (5 mL),NaN₃ (107 mg, 1.65 mmol), NH₄Cl (89 mg, 1.65 mmol) and LiCl (20 mg) wereadded and stirred at 100° C. for 14 h. After completion of the reaction,the reaction mixture was quenched with ice water and acidified with 2NHCl solution to pH=2. Precipitated solid was filtered and solid washedwith cold water to afford F (0.25 g, 70.6%) as an off white solid.LC-MS: m/z 280.20 [M+H]⁺.

N-(1-phenylcyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(1)

To a stirred solution of compound F (250 mg, 896 mmol) in DCM (5 mL),trifluoroacetic anhydride (TFAA, 225 mg, 1.07 mmol) was added at 0° C.and the reaction was allowed to stir at RT for 4 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was evaporated to dryness. The residue was dissolved insaturated solution of NaHCO₃ and extracted with 5% MeOH in DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography 20% EtOAc/hexane to affordcompound 1 (45 mg, 14.51%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H),8.95-8.85 (m, 2H), 7.25 (dd, J=8.4, 6.9 Hz, 2H), 7.22-7.07 (m, 3H),1.43-1.21 (m, 4H); LC-MS: m/z 348.05 [M+H]⁺; HPLC: 99.9%.

Example 2N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(2)

5-bromo-N-(1-phenylethyl)pyrimidin-2-amine (G)

To a stirred solution of 5-bromo-2-chloropyrimidine (C, 5 g, 26 mmol) inEtOH (20 mL), 1-phenylethan-1-amine (6.26 g, 52 mmol) in DIPEA (30 mL)was added at 90° C. and the reaction mixture was stirred at 90° C. for14 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was cooled to RT andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 10% EtOAc/hexane to affordcompound G (6 g, 83.68%) as a white solid. LC-MS: m/z 277.9 [M+H]⁺.

2-((1-phenylethyl)amino)pyrimidine-5-carbonitrile (H)

To a stirred solution of compound G (4 g, 14 mmol) in DMF, Zn(CN)₂ (2.52g, 21 mmol) was added and purged with argon for 20 min. Pd(PPh₃)₄(1.61g, 1.4 mmol) was added and again purged with argon for 20 min and thenstirred at 120° C. for 14 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasquenched with saturated aqueous NH₄Cl solution and extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 10% EtOAc/hexane toafford compound H (3 g, 92%) as an off white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.51 (s, 1H), 8.42 (s, 1H), 7.37-7.31 (m, 4H), 7.30-7.27 (m,1H), 6.02 (d, J=7.2 Hz, 1H), 5.28-5.20 (m, 1H), 1.61-1.56 (m, 3H).

N-(1-phenylethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (I)

To a stirred solution of compound H (0.7 g, 3.1 mmol) in DMF (10 mL),NaN₃ (0.6 g, 9.3 mmol), NH₄Cl (0.5 g, 9.3 mmol) and LiCl (50 mg) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was evaporated to dryness. The residuewas basified with 10% NaOH solution and extracted with EtOAc. Aqueouslayer was acidified with HCl solution to pH=2 and concentrated underreduced pressure. The residue was dissolved in 20% MeOH in DCM andstirred for 10 min, then the solution was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford compound I (600 mg,crude) as an off white solid. LC-MS: m/z 268.10 [M+H]⁺.

N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(2)

To a stirred solution of compound I (0.4 g, 1.4 mmol) in DCM (5 mL),TFAA (0.3 mL, 2.2 mmol) was added and the reaction mixture was stirredat RT for 3 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with icewater and extracted with DCM. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 3% MeOH/DCM to afford compound 2 (0.1 g, 20%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (dd, J=17.0, 9.7 Hz, 3H),7.40 (d, J=7.6 Hz, 2H), 7.31 (t, J=7.5 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H),5.24-5.18 (m, 1H), 1.49 (d, J=7.0 Hz, 3H); LC-MS: m/z 336.05 [M+H]⁺;HPLC Purity: 99.35%.

Example 3 N-((6-methylpyridin-2-yl)methyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (3)

5-bromo-N-((6-methylpyridin-2-yl)methyl)pyrimidin -2-amine (J)

To a stirred solution of (6-methylpyridin-2-yl)methanamine (0.2 g, 1.63mmol) in ethanol (5 mL), 5-bromo-2-chloropyrimidine (C, 0.4 g, 2.07mmol) and DIPEA (0.9 mL, 4.91 mmol) were added and the reaction mixturewas heated to 90° C. for 4 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 10% EtOAc/hexane to affordcompound J (0.15 g, 32%) as an off white solid. LC-MS: m/z 278.95[M+H]⁺.

2-(((6-methylpyridin-2-yl)methyl)amino)pyrimidine-5-carbonitrile (K)

A stirred solution of compound J (0.15 g, 0.53 mmol) and Zn(CN)₂ (0.28g, 2.42 mmol) in DMF (2 mL) was purged with argon for 20 min and thenPd(PPh₃)₄(0.093 g, 0.08 mmol) was added. The reaction mixture wasfurther purged with argon for 20 min and then stirred at 110° C. for 12h. After completion of the reaction, the reaction mixture was quenchedwith ice water and filtered through Celite and washed with EtOAc. Thefiltrate was concentrated under reduced pressure. The residue wassuspended in water and the obtained solid was filtered and dried toafford compound K (0.15 g, crude) as a white powder. LC-MS: m/z226.05[M+H]⁺.

N-((6-methylpyridin-2-yl)methyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(L)

To a stirred solution of compound K (0.15 g, 0.66 mmol) in DMF (3 mL),NaN₃ (0.13 g, 2 mmol), NH₄Cl (0.1 g, 2 mmol) and LiCl (20 mg) were addedand the reaction mixture was stirred at 100° C. for 14 h. The progressof the reaction was monitored by TLC. After completion of the reaction,the reaction mixture was quenched with ice water and acidified with 2NHCl solution to pH=2, extracted with 10% MeOH/DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound L (0.14 g, crude)as a white solid. LC-MS: m/z 269.05 [M+H]⁺.

N-((6-methylpyridin-2-yl)methyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (3)

To a stirred solution of compound L (0.14 g, 0.52 mmol) in DCM (2 mL),TFAA (0.4 mL, 2.64 mmol) was added and the reaction mixture was stirredat RT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in water and extracted withEtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 80%EtOAc/hexane to afford compound 3 (0.05 g, 28%) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.96-8.83 (m, 2H), 8.77 (t, J=6.3 Hz, 1H),7.62 (t, J=7.7 Hz, 1H), 7.10 (dd, J=13.2, 7.7 Hz, 2H), 4.65 (d, J=6.3Hz, 2H), 2.45 (s, 3H). LC-MS: m/z 337.05 [M+H]⁺; HPLC Purity: 95.69%.

Example 45-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylcyclopropyl)pyrimidin-2-amine(4)

ethyl 2-((1-phenylcyclopropyl)amino)pyrimidine-5-carboxylate (N)

To a stirred solution of compound B (2 g, 10.7 mmol) in ethanol (20 mL),DIPEA (9 mL, 53 mmol) and compound M (1.42 g, 10.7 mmol) were added andthe reaction mixture was stirred at 90° C. for 8 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound N (2.7 g, 88.8%) as an off white solid.¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.85 (s, 1H), 7.24-7.14 (m, 5H),6.35 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 1.48-1.32 (m, 7H).

2-((1-phenylcyclopropyl)amino)pyrimidine-5-carboxylic Acid (O)

To a stirred solution of compound N (2.77 g, 9.5 mmol) in ethanol:water(20 mL:20 mL), NaOH (0.76 g, 19 mmol) was added and the reaction mixturewas stirred at 60° C. for 2 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas neutralized with 2N HCl solution and extracted with EtOAc. Theorganic layer was separated and washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by trituration using ether and pentane to afford of compound O(2.2 g, 90.16%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s,1H), 8.83 (s, 1H), 8.70 (d, J=17.2 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.14(d, J=8.1 Hz, 3H), 1.34-1.21 (m, 4H).

Tert-butyl 2-(2-((1-phenylcyclopropyl)amino)pyrimidine-5-carbonyl)hydrazine-1-carboxylate (P)

To a stirred solution of compound O (1.0 g, 3.90 mmol) in DCM (10 mL),tert-butyl hydrazinecarboxylate (0.56 g, 4.29 mmol), HATU (1.78 g, 4.68mmol) and DIPEA (0.75 g, 5.85 mmol) were added at 0° C. under nitrogenatmosphere and stirred at room temperature for 12 h. After consumptionof the starting material (by TLC), the reaction mixture was quenchedwith water and extracted with EtOAc. The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography to affordcompound P (0.9 g, 62.5%) as a pale yellow oil. LC-MS: m/z 370.1 [M+H]⁺.

2-((1-phenylcyclopropyl)amino)pyrimidine-5-carbohydrazide (Q)

To a stirred solution of compound P (0.9 g, 2.43 mmol) in DCM (12 mL),TFA (0.8 mL) was added and stirred at room temperature for 2 h. Aftercomplete consumption of the starting material (by TLC), the reactionmixture was concentrated under reduced pressure to obtain the product asa TFA salt. The salt was basified with NaHCO₃ solution and extractedwith 15% MeOH/DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 5%MeOH/DCM to afford Q (0.6 g, 91.4%) as an off white solid. LC-MS: m/z270.15 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylcyclopropyl)pyrimidin-2-amine(4)

To a stirred solution of compound Q (0.3 g, 1.11 mmol) in toluene (5mL), 2,2-difluoroacetic anhydride (0.13 mL, 1.11 mmol) was added. Thereaction mixture was stirred at RT for 30 min and then stirred at 70° C.for 17 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford 4 (80 mg, 21.8%) as anoff white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.93-8.82 (m,2H), 7.52 (s, 1H), 7.25 (t, J=7.6 Hz, 2H), 7.15 (dd, J=16.9, 7.8 Hz,3H), 1.37-1.24 (m, 4H); LC-MS: m/z 330.1 [M+H]⁺; HPLC Purity: 99.7%.

Example 55-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)pyrimidin-2-amine(5)

1-(4-fluorophenyl)cyclopropan-1-amine (S)

To a stirred solution of 4-fluorobenzonitrile (R, 10 g, 82.64 mmol) indiethyl ether (200 mL), ethyl magnesium bromide (3M in THF, 60.6 mL,181.81 mmol) and titanium isopropoxide (25.81 g, 90.9 mmol) were addedat −70° C. and the reaction mixture was stirred at RT for 2 h. BF₃.OEt₂(23.47 g, 165.28 mmol) was added at 0° C. and stirred at RT for 8 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with NH₄Cl solution,basified with 10% NaOH solution, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 70% EtOAc/hexane toafford compound S (4.5 g, 36.08%) as a thick oil. ¹H NMR (400 MHz,DMSO-d₆) δ 7.37-7.30 (m, 2H), 7.09-7.04 (m, 2H), 2.92 (bs, 2H),0.95-0.82 (m, 4H); LC-MS: m/z 151.95 [M+H]⁺.

ethyl 2-((1-(4-fluorophenyl)cyclopropyl)amino)pyrimidine-5-carboxylate(T)

To a stirred solution of 1-(4-fluorophenyl)cyclopropan-1-amine (S, 0.7g, 4.63 mmol) in EtOH (10 mL), ethyl 2-chloropyrimidine-5-carboxylate(M, 1.03 g, 5.56 mmol) and DIPEA (2.5 mL, 13.9 mmol) were added at RTand the reaction mixture was stirred at 90° C. for 12 h. The progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 10% EtOAc/hexane toafford compound T (0.7 g, 50.1%) as a white solid. LC-MS: m/z 302.1[M+H]⁺.

2-((1-(4-fluorophenyl)cyclopropyl)amino)pyrimidine-5-carbohydrazide (U)

To a stirred solution of compound T (0.4 g, 1.32 mmol) in EtOH (10 mL),hydrazine hydrate (2 mL) was added and the reaction mixture was stirredat 90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound U (0.3 g,78.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.95 (s, 1H),8.65-8.61 (m, 2H), 8.57 (s, 1H), 7.19 (t, J=8.8 Hz, 2H), 7.04 (t, J=8.8Hz, 2H), 4.39 (s, 2H), 1.27-1.18 (m, 4H); LC-MS: m/z 288.05 [M+H]⁺.

N′-(2,2-difluoroacetyl)-2-((1-(4-fluorophenyl)cyclopropyl)amino)pyrimidine-5-carbohydrazide(V)

To a stirred solution of compound U (0.3 g, 1.14 mmol) in toluene (10mL), 2,2-difluoroacetic anhydride (0.18 mL, 1.56 mmol) was added.Reaction mixture was stirred at RT for 30 min and then stirred at 90° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 5% MeOH/DCM to afford compound V (0.2 g, 55.2%) asa thick oil. LC-MS: m/z 365.85 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)pyrimidin-2-amine(5)

To a stirred solution of compound V (0.1 g, 0.27 mmol) in THF (2 mL),Burgess reagent (0.13 g, 0.54 mmol) was added and the reaction mixturewas stirred at 80° C. for 30 min in microwave. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound 5 (0.035g, 36.8%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s,1H), 8.88 (d, J=8.2 Hz, 2H), 7.45 (t, J=51.4 Hz, 1H), 7.23 (dd, J=8.6,5.4 Hz, 2H), 7.07 (t, J=8.7 Hz, 2H), 1.35-1.21 (m, 4H); LC-MS: m/z348.10 [M+H]⁺; HPLC Purity: 99.7%.

Example 65-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylethyl)pyrimidin-2-amine(6)

5-bromo-N-(1-phenylethyl)pyrimidin-2-amine (X)

To a stirred solution of 1-phenylethan-1-amine (W, 5.0 g, 26.0 mmol) inEtOH (20 mL), 5-bromo-2-chloropyrimidine (C, 6.26 g, 52.0 mmol) andDIPEA (30 mL, 156 mmol) were added and the reaction mixture was heatedto 90° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% EtOAc/hexane to afford compound X (6.0 g,83.6%) as a brown oil. LC-MS: m/z 278.20 [M+H]⁺.

2-((1-phenylethyl)amino)pyrimidine-5-carbonitrile (Y)

To a stirred solution of compound X (4.0 g, 14.0 mmol) in dry DMF (20mL), zinc cyanide (2.52 g, 21.0 mmol) was added and the suspension waspurged with nitrogen gas for 20 min. Pd(PPh₃)₄ (1.61 g, 1.40 mmol) wasadded and the suspension was again purged with nitrogen for 20 min. Thereaction mixture was stirred at 120° C. for 14 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through a pad of Celite and washed withEtOAc. The combined organic layer was washed with cold water, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 10%EtOAc/hexane to afford compound Y (3 g, 92.8%) as a thick oil. LC-MS:m/z 225.15 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.42 (s,1H), 7.39-7.27 (m, 5H), 6.03 (d, J=7.2 Hz, 1H), 5.28-5.20 (m, 1H), 1.60(d, J=6.8 Hz, 3H).

N-(1-phenylethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (Z)

To a stirred solution of compound Y (0.7 g, 3.10 mmol) in DMF (10 mL),NaN₃ (0.60 g, 9.30 mmol), NH₄Cl (0.5 g, 9.30 mmol) and LiCl (50 mg) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered, washed with water, driedto afford compound Z (0.7 g, crude) as a thick oil. LC-MS: m/z 268.05[M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylethyl)pyrimidin-2-amine(6)

To a stirred solution of compound Z (0.7 g, 2.60 mmol) in DCM (15 mL),2,2-difluoroacetic anhydride (0.4 mL, 3.90 mmol) was added at 0° C. andthe reaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20%EtOAc/hexane to afford compound 6 (0.2 g, 24%) as an off white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.84 (d, J=12.4 Hz, 2H), 8.76 (d, J=8.3 Hz,1H), 7.51 (t, J=51.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.31 (t, J=7.5 Hz,2H), 7.21 (t, J=7.3 Hz, 1H), 5.25-5.18 (m, 1H), 1.49 (d, J=7.0 Hz, 3H);LC-MS: m/z 317.95 [M+H]⁺; HPLC Purity: 99.1%.

Example 7N-benzhydryl-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(7)

Diphenylmethanamine (AB)

To a stirred solution of diphenylmethanimine (AA, 1.5 g, 8.28 mmol) inMeOH (20 mL), NaBH₄ (0.47 g, 12.4 mmol) was added and the reactionmixture was stirred at RT for 3 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The reaction mixture wasdiluted with water and extracted with 10% MeOH/DCM. The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford compound AB (0.8 g, 53%) as a thick oil. ¹HNMR (400 MHz, DMSO-d₆) δ 7.82-7.78 (m, 4H), 7.36-7.29 (m, 4H), 7.25-7.16(m, 2H), 5.08 (s, 1H), 2.23 (s, 2H).

ethyl 2-(benzhydrylamino)pyrimidine-5-carboxylate (AC)

To a stirred solution of compound AB (0.7 g, 3.76 mmol) in ethanol (10mL), ethyl 2-chloropyrimidine-5-carboxylate (0.68 g, 3.76 mmol) andDIPEA (1.45 g, 11.9 mmol) were added at 80° C. and the reaction mixturewas stirred at 90° C. for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 20% EtOAc/hexane to affordcompound AC (0.5 g, 40%) as a white solid. LC-MS: m/z 334.05 [M+H]⁺.

2-(benzhydrylamino)pyrimidine-5-carbohydrazide (AD)

To a stirred solution of compound AC (0.5 g, 1.50 mmol) in ethanol (10mL), hydrazine hydrate (3 mL) was added and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 5% MeOH/DCM to afford compound AD(0.3 g, 62.7%) as a white solid. LC-MS: m/z 320.05 [M+H]⁺.

N-benzhydryl-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(7)

To a stirred solution of compound AD (0.3 g, 0.94 mmol) in toluene (5mL), 2,2-difluoroacetic anhydride (0.19 g, 1.12 mmol) was added. Thereaction mixture was stirred at RT for 30 min and then stirred at 80° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford compound 7 (0.085 g,23.8%) as a thick oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (d, J=9.3 Hz,1H), 8.91 (d, J=5.4 Hz, 2H), 7.52 (s, 1H), 7.45-7.37 (m, 4H), 7.33 (dd,J=8.5, 6.8 Hz, 4H), 7.29-7.20 (m, 2H), 6.52 (d, J=9.2 Hz, 1H); LC-MS:m/z 380.10 [M+H]⁺; HPLC Purity: 95.2%.

Example 85-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-N-methylpyrimidin-2-amine(8)

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-N-methylpyrimidin-2-amine(8)

To a stirred solution of compound 5 (0.18 g, 5.2 mmol) in THF (2 mL),NaH (60%, 12 mg, 5.2 mmol) was added and the reaction mixture wasstirred at 0° C. for 20 min. MeI (0.032 mL, 5.2 mmol) was added at 0° C.and the reaction mixture was stirred at RT for 1 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 10% EtOAc/hexane to affordcompound 8 (70 mg, 37.4%) as an off white solid; ¹H NMR (400 MHz,DMSO-d₆) δ 8.96 (d, J=19.8 Hz, 2H), 7.52 (t, J=51.6 Hz, 1H), 7.12-7.05(m, 4H), 3.29 (s, 3H), 1.44 (s, 4H); LC-MS: m/z 362 [M+H]⁺; HPLC Purity:99.3%.

Example 95-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)pyrimidin-2-amine(9)

2-((2-(4-fluorophenyl)propan-2-yl)amino)pyrimidine-5-carbonitrile (AG)

To a stirred solution of 2-(4-fluorophenyl)propan-2-amine (AE, 0.5 g,32.0 mmol) in ethanol (15 mL), 2-chloropyrimidine-5-carbonitrile (AF,0.6 g, 4.20 mmol) and DIPEA (2.7 mL, 16.0 mmol) were added and thereaction mixture was stirred at 90° C. for 14 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 10%EtOAc/hexane to afford compound AG (0.58 g, 69.3%) as a white solid.LC-MS: m/z 257.05 [M+H]⁺.

N-(2-(4-fluorophenyl)propan-2-yl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(AH)

To a stirred solution of compound AG (0.58 g, 2.20 mmol) in DMF (10 mL),NaN₃ (0.44 g, 6.70 mmol), NH₄Cl (0.35 g, 6.70 mmol) and LiCl (90 mg)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingaqueous HCl solution. The obtained solid was filtered, washed withwater, dried to afford compound AH (0.6 g, crude) as an off white solid.LC-MS: m/z 300.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)pyrimidin-2-amine(9)

To a stirred solution of compound AH (0.6 g, 2.0 mmol) in DCM (15 mL),2,2-difluoroacetic anhydride (0.32 mL, 3.0 mmol) was added and thereaction mixture was stirred at RT for 16 h.

The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was quenched with water and extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20%EtOAc/hexane to afford compound 9 (0.06 g, 8.5%) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.62 (s, 1H), 8.48 (s, 1H),7.38-7.35 (m, 2H), 7.48 (s, 1H), 7.07 (t, J=7.2 Hz, 2H), 1.70 (s, 6H).LC-MS: m/z 350.0 [M+H]⁺; HPLC Purity: 98.3%.

Example 105-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)cyclopropyl)pyrimidin-2-amine(10)

1-(2,4-difluorophenyl)cyclopropan-1-amine (AJ)

To a stirred solution of 2,4-difluorobenzonitrile (AI, 2.0 g, 28.7 mmol)in dry diethyl ether (250 mL), EtMgBr (10.5 mL, 3M solution in THF, 63.3mmol) and Ti(O-iPr)₄ (4.5 g, 31.5 mmol) were added at −78° C. BF₃.Et₂O(10.7 mL, 57.4 mmol) was added and the reaction mixture was allowed tostirred at RT for 12 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith NH₄Cl solution and extracted with EtOAc. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 30% EtOAc/hexane to afford compound AJ (1.0g, 20%) as a pale yellow oil. LC-MS: m/z 170 [M+1]⁺.

5-bromo-N-(1-(2,4-difluorophenyl)cyclopropyl)pyrimidin-2-amine (AK)

To a stirred solution of compound AJ (0.5 g, 2.95 mmol) in ethanol (10mL), DIPEA (1.5 mL, 8.85 mmol) and 5-bromo-2-chloropyrimidine (C, 0.85g, 4.43 mmol) were added and the reaction mixture was stirred at 90° C.for 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography 10% EtOAc/hexane to afford compound AK (0.65 g, 67%) as athick oil; LC-MS: m/z 327.89 [M+1]⁺.

2-((1-(2,4-difluorophenyl)cyclopropyl)amino)pyrimidine-5-carbonitrile(AL)

A stirred solution of compound 4 (0.64 g, 1.96 mmol) and Zn(CN)₂ (0.91g, 7.84 mmol) in DMF (10 mL) was purged for 20 min and thenPd(PPh₃)₄(0.34 g, 0.29 mmol) was added. The reaction mixture was furtherpurged with argon for 20 min. The reaction mixture was stirred at 110°C. for 12 h. After completion of the reaction, the reaction mixture wasquenched with ice water, filtered through Celite bed, and washed withEtOAc. The filtrate was concentrated under reduced pressure. The residuewas dissolved in water and obtained solid was filtered, dried to affordcompound AL (0.5 g, crude) as a white powder. LC-MS: m/z 272.96 [M+H]⁺.

N-(1-(2,4-difluorophenyl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(AM)

To a stirred solution of compound AL (0.5 g, 1.80 mmol) in DMF (10 mL),NaN₃ (0.5 g, 9.19 mmol), NH₄Cl (0.6 g, 9.19 mmol) and LiCl (150 mg) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water and acidifiedwith 2N HCl solution to pH=2. The precipitated solid was filtered andwashed with cold water to afford compound AM (0.4 g, 69%) as a whitesolid. LC-MS: m/z 316 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)cyclopropyl)pyrimidin-2-amine(10)

To a stirred solution of compound AM (0.25 g, 0.79 mmol) in DCM (10 mL),2,2-difluoroacetic anhydride (0.46 mL, 3.96 mmol) was added at 0° C. andthe reaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and extracted with DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 10% MeOH/DCM toafford compound 10 (0.08 g, 27.6%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.04 (s, 1H), 8.82 (d, J=7.2 Hz, 2H), 7.69-7.64 (m, 1H), 7.18(t, J=8.0 Hz, 1H), 6.99 (t, J=8.2 Hz, 2H), 1.30-1.27 (m, 2H), 1.23-1.20(m, 2H), LC-MS: m/z 366.03 [M+H]⁺; HPLC Purity: 99%.

Example 115-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)pyrimidin-2-amine(11)

1-(2,6-difluorophenyl)cyclopropan-1-amine (AO)

To a stirred solution of 2,6-difluorobenzonitrile (AN, 2.0 g, 14.3 mmol)in dry THF (50 mL), EtMgBr (10.5 mL, 3M solution in THF, 31.6 mmol) andTi(O-iPr)₄ (4.67 mL, 15.8 mmol) were added at 0° C. BF₃.Et₂O (4.08 g,28.7 mmol) was added and the reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with NH₄Cl solutionand extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 60% EtOAc/hexane to afford compound AO (1.2 g, 50%)as a pale yellow oil. LC-MS: m/z 170 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ7.32-7.25 (m, 1H), 7.04-6.97 (m, 2H), 2.26 (s, 2H), 0.90-0.75 (m, 4H).

2-((1-(2,6-difluorophenyl)cyclopropyl)amino)pyrimidine-5-carbonitrile(AP)

To a stirred solution of compound AO (0.8 g, 4.73 mmol) in Ethanol (10mL), DIPEA (40 mL, 23.6 mmol) and 2-chloropyrimidine-5-carbonitrile (AF,0.85 g, 6.15 mmol) were added and the reaction mixture was stirred at90° C. for 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 10% EtOAc/hexane to afford compound AP (1.1 g, 85%)as a thick oil. LC-MS: m/z 273.05 [M+1]⁺.

N-(1-(2,6-difluorophenyl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(AQ)

To a stirred solution of compound AP (0.7 g, 2.57 mmol) in DMF (10 mL),NaN₃ (0.7 g, 12.8 mmol), NH₄Cl (0.83 g, 12.8 mmol) and LiCl (210 mg)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water and acidifiedwith 2N HCl solution to pH=2. The precipitated solid was filtered andsolid washed with cold water to afford compound AQ (0.52 g, 64%) as awhite solid. LC-MS: m/z 316.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)pyrimidin-2-amine(11)

To a stirred solution of compound AP (0.5 g, 1.58 mmol) in DCM (15 mL),2,2-difluoroacetic anhydride (0.24 mL, 2.38 mmol) was added at 0° C. andthe reaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and extracted with DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 12% EtOAc/hexane toafford compound 11 (0.35 g, 61.3%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.82 (s, 2H), 7.51 (t, J=51 Hz, 1H), 7.32-7.28(m, 1H), 6.99 (t, J=8.2 Hz, 2H), 1.30-1.27 (m, 2H), 1.23-1.20 (m, 2H),LC-MS: m/z 366 [M+H]⁺; HPLC Purity: 99.7%.

Example 122-(difluoromethyl)-5-(2-(1-phenylcyclopropoxy)pyrimidin-5-yl)-1,3,4-oxadiazole(12)

1-phenylcyclopropan-1-ol (AS)

To a stirred solution of ethyl benzoate (AR, 10 g, 73.4 mmol) in THF(120 mL), EtMgBr (3M in THF, 68.5 mL, 205.6 mmol) and Ti(OPr-i)₄ (29.2g, 102.76 mmol) were added and the reaction mixture was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated aqueous NH₄Cl solution and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 20% EtOAc/hexane to affordcompound AS (2.5 g, 25.5%) as a colorless liquid. LC-MS: m/z 134.86[M+H]⁺.

5-bromo-2-(methylthio)pyrimidine (AT)

To a stirred solution of 5-bromo-2-chloropyrimidine (C, 9 g, 46.5 mmol)in EtOH (50 mL), sodium thiomethoxide (3.25 g, 46.5 mmol) was added andthe reaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound AT(8.7 g, crude) as an off white solid. LC-MS: m/z 204.85 [M+H]⁺.

5-bromo-2-(methylsulfonyl)pyrimidine (AU)

To a stirred solution of compound AT (8.7 g, 42.4 mmol) in MeOH:H₂O(1:1, 70 mL), oxone (12.9 g, 84.8 mmol) was added and the reactionmixture was stirred at RT for 4 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas diluted with DCM and aqueous layer was extracted with DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound AU(9.6 g, crude) as an off white solid. LC-MS: m/z 237.00 [M+H]⁺.

5-bromo-2-(1-phenylcyclopropoxy)pyrimidine (AV)

To a stirred solution of compound AS (3 g, 22.3 mmol) in DMF (25 mL),Cs₂CO₃ (14.5 g, 44.6 mmol) and compound AU (4.75 g, 20.0 mmol) wereadded at 0° C. and the reaction mixture was stirred at 0° C. for 3 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was diluted with water and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 10%EtOAc/hexane to afford compound AV (3 g, 46%) as an off white solid.LC-MS: m/z 292.87 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.54-8.45 (m, 2H),7.42-7.19 (m, 5H), 1.56-1.26 (m, 4H).

ethyl 2-(1-phenylcyclopropoxy)pyrimidine-5-carboxylate (AW)

To a stirred solution of compound AV (3 g, 10.3 mmol) in DMF:EtOH (1:1,30 mL), Pd(PPh₃).Cl₂ (1.51 g, 2.16 mmol) was added. The suspension waspurged with argon for 30 min and then triethyl amine (3.58 mL, 25.7mmol) was added. The reaction mixture was stirred at 100° C. for 4 hunder carbon monoxide pressure. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas diluted with EtOAc and washed with water. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAC/hexane to afford compound AW (1 g,34.2%) as an off white solid. LC-MS: m/z 285.08 [M+H]⁺.

2-(1-phenylcyclopropoxy)pyrimidine-5-carboxylic Acid (AX)

To a stirred solution of compound AW (1 g, 3.51 mmol) in EtOH (20 mL),NaOH (0.28 g, 7.0 mmol) in water was added at 0° C. and the reactionmixture was at RT for 1 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The reaction mixture was dilutedwith water and acidified with HCl to pH=5. The solid obtained wasfiltered and dried to afford compound AX (0.54 g, crude) as an off whitesolid. LC-MS: m/z 257.00 [M+H]⁺.

tert-butyl2-(2-(1-phenylcyclopropoxy)pyrimidine-5-carbonyl)hydrazine-1-carboxylate(AY)

To a stirred solution of compound AX (0.52 g, 2.02 mmol) in DCM (25 mL),tert-butyl hydrazinecarboxylate (0.32 g, 2.43 mmol), HATU (0.92 g, 2.43mmol), DIPEA (1 mL, 6.06 mmol) were added at 0° C. and the reactionmixture was stirred at RT for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas diluted with water and extracted with DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAC/hexane to affordcompound AY (0.3 g, 39.9%) as an off white solid. LC-MS: m/z 371.05[M+H]⁺.

2-(difluoromethyl)-5-(2-(1-phenylcyclopropoxy)pyrimidin-5-yl)-1,3,4-oxadiazole(12)

To a stirred solution of compound AY (0.27 g, 0.72 mmol) in THF (10 mL),Burgess reagent (0.43 g, 1.82 mmol) and DFAA (0.5 mL) were added at 0°C. The reaction mixture was stirred at RT for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound 12 (0.07 g, 31%) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 2H), 7.56 (t, J=51.2 Hz, 1H),7.29-7.27 (m, 2H), 7.23-7.21 (m, 3H), 1.49-1.44 (m, 4H), LC-MS: m/z331.08 [M+H]⁺; HPLC Purity: 98.8%.

Example 135-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-l-(4-fluorophenyl)propyl)pyrimidin-2-amine (13)

2-((3,3,3-trifluoro-l-(4-fluorophenyl)propyl)amino)pyrimidine-5-carbonitrile(BA)

To a stirred solution of3,3,3-trifluoro-1-(4-fluorophenyl)propan-1-amine (AZ, 0.4 g, 1.90 mmol)in EtOH (10 mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.35 g, 2.50mmol) and DIPEA (1.6 mL, 9.50 mmol) were added and the reaction mixturewas stirred at 90° C. for 14 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 10% EtOAc/hexane to affordcompound BA (0.55 g, 91.6%) as a white solid. LC-MS: m/z 311 [M+H]⁺.

5-(1H-tetrazol-5-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine(BB)

To a stirred solution of compound BA (0.55 g, 1.70 mmol) in DMF (7 mL),NaN₃ (0.35 g, 5.30 mmol), NH₄Cl (0.27 g, 5.30 mmol) and LiCl (50 mg)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered, washed with water, anddried to afford compound BB (0.5 g, crude) as an off white solid. LC-MS:m/z 354.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine(13)

To a stirred solution of compound BB (0.5 g, 1.40 mmol) in DCM (15 mL),2,2-difluoroacetic anhydride (0.22 mL, 2.10 mmol) was added and thereaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and extracted with DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 20% EtOAc/hexane toafford compound 13 (0.06 g, 8.5%) as colorless sticky liquid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.92 (d, J=9.2 Hz, 1H), 8.88 (s, 2H), 7.52 (t, J=7Hz, 3H), 7.19 (d, J=8.6 Hz, 2H), 5.57-5.51 (m, 1H), 3.02-2.96 (m, 1H),2.85-2.79 (m, 1H). LC-MS: m/z 403.97 [M+H]⁺; HPLC Purity: 99.7%.

Example 145-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropyl)pyrimidin-2-amine(14)

4′-fluoro-[1,1′-biphenyl]-2-carbonitrile (BE)

To a stirred solution of 2-bromobenzonitrile (BC, 4 g, 10.9 mmol) indioxane:water (13 mL), K₂CO₃ (3.03 g, 21.9 mmol) and(4-fluorophenyl)boronic acid (BD, 1.84 g, 13.1 mmol) were added andpurged under argon atmosphere for 10 min. Pd(dppf)C12 (0.89 g, 1.09mmol) was added and the reaction mixture was stirred at 90° C. for 12 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was quenched with water and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using 10% EtOAc/hexane toafford compound BE (2.0 g, 92.5%) as an off white solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.95-7.93 (m, 1H), 7.80-7.76 (m, 1H), 7.65-7.56 (m, 4H),7.40-7.35 (m, 2H).

1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropan-1-amine (BF)

To a stirred solution of compound BE (0.5 g, 2.53 mmol) in dry Et₂O (10mL), EtMgBr (1.86 mL, 3M solution in THF, 5.58 mmol) and Ti(O-iPr)₄(0.79 g, 2.79 mmol) were added at 0° C. and the reaction mixture wasstirred at RT for 1 h. BF₃.OEt₂ (0.72 g, 2.79 mmol) was added and thereaction mixture was stirred at RT for 2 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was quenched with saturated aqueous NH₄Cl solution and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20%EtOAc/hexane to afford compound BF (0.9 g, 39%) as a pale yellow oil.LC-MS: m/z 227.90 [M+H]⁺.

2-((1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropyl)amino)pyrimidine-5-carbonitrile(BG)

To a stirred solution of compound BF (0.55 g, 3.96 mmol) in EtOH (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.9 g, 3.96 mmol) and DIPEA(1.53 g, 11.9 mmol) were added at 80° C. and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 20% EtOAc/hexane to affordcompound BG (0.5 g, 38.4%) as a yellow oil. LC-MS: m/z 331.08 [M+H]⁺.

N-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(BH)

To a stirred solution of compound BG (0.5 g, 1.51 mmol) in DMF (10 mL),NaN₃ (0.29 g, 4.54 mmol), NH₄Cl (0.24 g, 4.54 mmol) and LiCl (70 mg)were added and the reaction mixture was stirred at 90° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water and acidifiedwith 2N HCl solution to pH=2, extracted with 10% MeOH/DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound BH (0.3 g, 53%)as a white solid. LC-MS: m/z 374.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropyl)pyrimidin-2-amine (14)

To a stirred solution of compound BH (0.3 g, 0.8 mmol) in DCM (10 mL),DFAA (0.29 g, 1.20 mmol) was added at 0° C. and the reaction mixture wasstirred at RT for 16 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith water and extracted with DCM. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 10% EtOAc/hexane to afford compound 14 (55 mg, 16%)as a thick oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.80 (s, 1H),7.95 (d, J=7.2 Hz, 1H), 7.91 (s, 1H), 7.51 (d, J=53.7 Hz, 1H), 7.41-7.37(m, 2H), 7.32-7.23 (m, 4H), 7.09-7.07 (m, 1H), 1.07-1.04 (m, 2H),1.01-0.98 (m, 2H), LC-MS: m/z 424.07 [M+H]⁺; HPLC Purity: 99.8%.

Example 155-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(15)

2-((2,2,2-trifluoro-l-(4-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(BJ)

To a stirred solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine(1BI 0.5 g, 2.59 mmol) in EtOH (10 mL),2-chloropyrimidine-5-carbonitrile (AF, 0.47 g, 3.36 mmol) and DIPEA(2.19 mL, 12.9 mmol) were added and the reaction mixture was stirred at90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 10% EtOAc/hexane to afford compound BJ (0.17g, 22.1%) as a white solid.

5-(1H-tetrazol-5-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(BK)

To a stirred solution of compound BJ (0.17 g, 0.57 mmol) in DMF (10 mL),NaN₃ (0.18 g, 2.87 mmol), NH₄Cl (0.15 g, 2.87 mmol) and LiCl (50 mg)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered and washed with water,dried to afford compound BK (0.18 g, crude) as an off white solid.LC-MS: m/z 340.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(15)

To a stirred solution of compound BK (0.17 g, 4.40 mmol) in DCM (20 mL),2,2-difluoroacetic anhydride (0.12 mL, 8.90 mmol) was added and thereaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion, the reaction mixturewas quenched with water and extracted with DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 20% EtOAc/hexane to affordcompound 15 (0.027 g, 3.5%) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.57 (d, J=10.4 Hz, 1H), 8.99 (d, J=10.4 Hz, 2H), 7.80-7.78(m, 2H), 7.54 (t, J=51 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 6.27-6.20 (m,1H); LC-MS: m/z 390 [M+H]⁺; HPLC Purity: 99.7%.

Example 165-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropyl)pyrimidin-2-amine (16)

4′-fluoro-[1,1′-biphenyl]-4-carbonitrile (BN)

To a stirred solution of 4-bromobenzonitrile (BL, 2.0 g, 10.9 mmol) indioxane:Water (13 mL), K₂CO₃ (3.03 g, 21.9 mmol) and2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BM, 2.92 g,13.1 mmol) was added and the suspension was purged with argon for 10min. Pd(dppf)Cl₂. (0.89 g, 1.09 mmol) was added and the reaction mixturewas stirred at 90° C. for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water and extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography using 10% EtOAc/hexane to afford compound BN (2.0g, 92.5%) as an off white solid. LC-MS: m/z 198 [M+H]⁺.

1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropan-1-amine (BO)

To a stirred solution of compound BN (2.0 g, 10.1 mmol) in dry Et₂O (30mL), EtMgBr (7.44 mL, 3M solution, 22.3 mmol) and Ti(O-iPr)₄ (3.17 g,11.1 mmol) were added at 0° C. and the reaction mixture was stirred atRT for 1 h. BF₃.OEt₂ (2.88 g, 20.3 mmol) was added and the reactionmixture was stirred at RT for 2 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with NH₄Cl solution and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 20% EtOAc/hexane to affordcompound BO (0.9 g, 39.1%) as a pale yellow oil. LC-MS: m/z 228.05[M+H]⁺.

2-((1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)pyrimidine-5-carbonitrile(BP)

To a stirred solution of compound BO (0.55 g, 3.96 mmol) in EtOH (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.9 g, 3.96 mmol) and DIPEA(1.53 g, 11.9 mmol) were added at 80° C. and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 20% EtOAc/hexane to affordcompound BP (0.5 g, 38.4%) as a yellow oil; LC-MS: m/z 331.08 [M+H]⁺

N-(1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(BQ)

To a stirred solution of compound BP (0.5 g, 1.51 mmol) in DMF (10 mL),NaN₃ (0.29 g, 4.54 mmol), NH₄Cl (0.24 g, 4.54 mmol) and LiCl (70 mg)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water and acidifiedwith 2N HCl solution to pH=2. The precipitated solid was filtered andwashed with cold water to afford compound BQ (0.3 g, 53%) as a whitesolid. LC-MS: m/z 374.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropyl)pyrimidin-2-amine (16)

To a stirred solution of compound BQ (0.5 g, 1.34 mmol) in pyridine (10mL), DFAA (0.21 mL, 2.01 mmol) was added at 0° C. and the reactionmixture was stirred at 80° C. for 14 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water and extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 5% MeOH/DCM to afford compound 16(40 mg, 7%) as a thick oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H),8.89 (d, J=2.8 Hz, 1H), 8.85 (d, J=2.8 Hz, 1H), 7.65-7.62 (m, 2H),7.52-7.50 (m, 3H), 7.38 (t, J=51.4 Hz, 1H), 7.26-7.21 (m, 3H), 1.38-1.30(m, 4H), LC-MS: m/z 424.05 [M+H]⁺; HPLC Purity: 97.8%.

Example 175-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(4-(4-fluorophenyl)-1-phenylpiperidin-4-yl)pyrimidin-2-amine(17)

2,2′-(phenylazanediyl)bis(ethan-1-ol) (BS)

To a stirred solution of aniline (BR, 5.0 g, 53.6 mmol) and2,2′-(phenylazanediyl)bis(ethan-1-ol) (8.6 g, 107 mmol) in water (70mL), CaCO₃ (10.7 g, 107 mmol) and KI (1.78 g, 10.7 mmol) were added andthe reaction mixture was stirred at 115° C. for 8 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with EtOAc and filtered through a pad ofCelite. The filtrate was concentrated under reduced pressure and thecrude product was purified by column chromatography using 30%EtOAc/hexane to afford compound BS (16.4 g, crude) as a white solid.LC-MS: m/z 181.9 [M+H]⁺.

N,N-bis(2-chloroethyl)aniline (BT)

A stirred solution of compound BS (9.0 g, 49.4 mmol) in POCl₃ (50 mL)was refluxed for 2 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in water and extracted with EtOAc. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 15% EtOAc/hexane to afford compound BT (6.1g, 57%) as a thick oil. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.25 (m, 2H),6.80-6.69 (m, 3H), 3.79-3.49 (m, 8H).

4-(4-fluorophenyl)-1-phenylpiperidine-4-carbonitrile (BU)

To a stirred solution of compound BT (6.1 g, 27.9 mmol) in DMF (70 mL),NaH (60% 3.35 g, 83.9 mmol) was added at 0° C. and the reaction mixturewas stirred for 10 min. To the resulting reaction mixture2-(4-fluorophenyl)acetonitrile (3.8 g, 27.9 mmol) was added and thereaction mixture was stirred at 60° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 20% EtOAc/hexane toafford compound BU (6.0 g, 77%) as a sticky solid.

4-(4-fluorophenyl)-1-phenylpiperidine-4-carboxamide (BV)

To a stirred solution of compound BU (6.0 g, 21.3 mmol) in DMSO (60 mL),K₂CO₃ (11.8 g, 85.4 mmol) and H₂O₂(30%, 9.6 mL, 85.4 mmol) were addedand the reaction mixture was stirred at 115° C. for 8 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with ice water and obtained solid wasfiltered, dried. The crude product was purified by column chromatographyusing 5% MeOH/DCM to afford compound BV (4 g, 63%) as a white solid.

4-(4-fluorophenyl)-1-phenylpiperidin-4-amine (BW)

To a stirred solution of compound BV (2.5 g, 8.36 mmol) in t-BuOH (30mL), NaOCl (1.74 g, 23.4 mmol) and 3N NaOH (15.5 mL) were added and thereaction mixture was stirred at RT for 14 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and the obtained solid wasfiltered and dried to afford compound BW (0.35 g, 86%). LC-MS: m/z 280[M+H]⁺.

2-((4-(4-fluorophenyl)-1-phenylpiperidin-4-yl)amino)pyrimidine-5-carbonitrile(BX)

To a stirred solution of compound BW (0.4 g, 2.86 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.77 g, 5.0 mmol) and DIPEA(2.6 mL, 14.3 mmol) were added and the reaction mixture was heated to90° C. for 4 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 50% EtOAc/hexane to afford compound BX (0.5 g, 50%)as an off white solid. LC-MS: m/z 374.05 [M+H]⁺.

N-(4-(4-fluorophenyl)-1-phenylpiperidin-4-yl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(BY)

To a stirred solution of compound BX (0.5 g, 1.33 mmol) in DMF (10 mL),NaN₃ (0.43 g, 6.68 mmol), NH₄Cl (0.36 g, 6.68 mmol) and LiCl (90 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound BY(0.53 g, 96%) as an off white solid. LC-MS: m/z 417.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(4-(4-fluorophenyl)-1-phenylpiperidin-4-yl)pyrimidin-2-amine(17)

To a stirred solution of compound BY (0.53 g, 1.27 mmol) in pyridine (10mL), DFAA (0.21 mL, 1.91 mmol) was added dropwise at 0° C. The reactionwas stirred at RT for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasquenched with water and extracted with DCM. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 12% EtOAc/hexane to afford compound 17 (31mg, 5.2%) as an off white solid. ¹H NMR (400 MHz, DMSO) δ 8.81 (br s,1H), 8.62 (br s, 1H), 8.56 (s, 1H), 7.43 (t, J=52 Hz, 1H), 7.42-7.40 (m,1H), 7.15 (t, J=8.0 Hz, 2H), 7.13 (t, J=8.4 Hz, 2H), 6.88 (d, J=8.0 Hz,2H), 6.70 (t, J=4.0 Hz, 1H), 3.35 (d, J=12.4 Hz, 2H), 2.94 (t, J=11.6Hz, 2H), 2.71 (d, J=12.4 Hz, 2H), 2.10-2.06 (m, 2H), 1.10 (s, 1H);LC-MS: m/z 467.14 [M+H]⁺; HPLC Purity: 99.7%.

Example 185-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)pyrimidin-2-amine(18)

4′-fluoro-[1,1′-biphenyl]-3-carbonitrile (CA)

To a stirred solution of 3-bromobenzonitrile (BZ, 2.0 g, 10.9 mmol) indioxane:water (13 mL), K₂CO₃ (3.03 g, 21.9 mmol) and2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BM, 2.92 g,13.1 mmol) were added and the suspension was purged with argon for 10min. Pd(dppf)C1₂ (0.89 g, 1.09 mmol) was added and the reaction mixturewas stirred at 90° C. for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water and extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography using 10% EtOAc/hexane to afford compound CA (2.0g, 92.6%) as an off white solid LC-MS: m/z 198.1[M+1]⁺.

1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropan-1-amine (CD)

To a stirred solution of compound CA (2.0 g, 10.1 mmol) in dry Et₂O (30mL), EtMgBr (3M in THF 7.44 mL, 3M solution, 22.3 mmol) and Ti(O-iPr)₄(3.17 g, 11.1 mmol) were added at 0° C. and the reaction mixture wasstirred at RT for 1 h. BF₃.OEt₂ (2.88 g, 20.3 mmol) was added and thereaction mixture was stirred at RT for 2 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was quenched with NH₄Cl solution and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 20% EtOAc/hexane toafford compound CD (0.9 g, 39.1%) as a pale yellow oil. LC-MS: m/z228.05 [M+1]⁺.

2-((1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)amino)pyrimidine-5-carbonitrile(CE)

To a stirred solution of compound CD (0.55 g, 3.96 mmol) in EtOH (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.9 g, 3.96 mmol) and DIPEA(1.53 g, 11.9 mmol) were added at 80° C. and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 20% EtOAc/hexane to affordcompound CE (0.6 g, 46%) as a yellow oil. LC-MS: m/z 331.10 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.72-8.69 (m, 2H), 7.66-7.62 (m,2H), 7.52 (d, J=8.0 Hz, 2H), 7.28-7.20 (m, 4H), 1.36-1.28 (m, 4H).

N-(1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(CF)

To a stirred solution of compound CE (0.6 g, 1.81 mmol) in DMF (70 mL),NaN₃ (0.35 g, 5.45 mmol), NH₄Cl (0.29 g, 5.45 mmol) and LiCl (70 mg)were added and the reaction mixture was stirred at 90° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound CF(0.5 g, 73%) as a white solid. LC-MS: m/z 374.05 [M+H]⁺.

N-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-2,2-difluoro-N-(1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)acetamide(CG)

To a stirred solution of compound CF (0.5 g, 1.34 mmol) in pyridine (5mL), DFAA (0.34 g, 2.01 mmol) was added at 0° C. and the reactionmixture was stirred at 80° C. for 4 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water and extracted with DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 10% EtOAc/hexane to affordcompound CG (0.3 g, 44%) as a thick oil LC-MS: m/z 424.07 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)pyrimidin-2-amine(18)

To a stirred solution of compound CG (0.3 g, 0.59 mmol) in ACN (5 mL),K₂CO₃ (0.2 g, 1.49 mmol) was added at 0° C. and the reaction mixture wasstirred at 80° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound 18 (0.11g, 43.4%) as a thick colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s,1H), 8.87 (dd, J=2.8, 2.4 Hz, 2H), 7.64-7.51 (m, 2H), 7.44 (s, 1H),7.39-7.32 (m, 3H), 7.29-7.19 (m, 3H), 1.49-1.42 (m, 2H), 1.32-1.30 (m,2H), LC-MS: m/z 424.07 [M+H]⁺; HPLC Purity: 98.1%.

Example 195-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-phenoxyethyl)pyrimidin-2-amine(19)

1-(4-fluorophenyl)-2-phenoxyethan-1-one (CI)

To a stirred solution of 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 3.0g, 13.8 mmol) in acetone (200 mL), K₂CO₃ (2.86 g, 20.7 mmol) and phenol(1.62 g, 17.2 mmol) were added and the reaction mixture was stirred at80° C. for 4 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 5% EtOAc/hexane to afford compound CI (1.5 g,47.3%) as an off white solid. LC-MS: m/z 231.01 [M+H]⁺.

(Z)-1-(4-fluorophenyl)-2-phenoxyethan-1-one oxime (CJ)

To a stirred solution of compound CI (1.28 g, 5.56 mmol) in EtOH (55mL), NH₂OH.HCl (0.96 g, 13.9 mmol) was added followed by addition ofpyridine (94 mL) and the reaction mixture was stirred at RT for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was diluted with 1N HCl solution topH=4 and extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford compound CJ (1.21 g, 88.2%) as an off white solidLC-MS: m/z 246 [M+H]⁺.

1-(4-fluorophenyl)-2-phenoxyethan-1-amine (CK)

To a stirred solution of CJ (1.2 g, 4.89 mmol) in MeOH (25 mL), Pd/C(150 mg) was added at RT and stirred for 16 h under H₂ atmosphere. Afterconsumption of the starting material (by TLC), the reaction mixture wasfiltered through celite bed and washed with MeOH. The filtrate wasconcentrated under reduced pressure afford compound CK (1.0 g, 77%) as athick oil. LC-MS: m/z 232 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-phenoxyethyl)amino)pyrimidine-5-carbonitrile(CL)

To a stirred solution of compound CK (0.5 g, 2.16 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.33 g, 2.38 mmol) and DIPEA(1.8 mL, 10.8 mmol) were added and the reaction mixture was heated to90° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound CL (0.62g, 86.8%) as a white solid. LC-MS: m/z 334.05 [M+H]⁺.

N-(1-(4-fluorophenyl)-2-phenoxyethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(CM)

To a stirred solution of compound CL (0.61 g, 1.80 mmol) in DMF (10 mL),NaN₃ (0.6 g, 9.2 mmol), NH₄Cl (0.5 g, 9.2 mmol) and LiCl (90 mg) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound CM(0.62 g, crude) as a thick oil. LC-MS: m/z 377.10 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-phenoxyethyl)pyrimidin-2-amine(19)

To a stirred solution of compound CM (0.5 g, 1.32 mmol) in DCM (10 mL),2,2-difluoroacetic anhydride (0.22 mL, 1.99 mmol) was added at 0° C.Reaction mixture was stirred at RT for 30 min and then stirred at 90° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford compound 19 (0.05 g,8.81%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (d, J=8.0Hz, 1H), 8.82 (d, J=8.4 Hz, 2H), 7.56-7.52 (m, 2H), 7.52 (t, J=51.2 Hz,1H), 7.27-7.20 (m, 4H), 6.94 (d, J=7.6 Hz, 3H), 5.58 (s, 1H), 4.42 (t,J=7.6 Hz, 1H), 4.25-4.22 (m, 1H); LC-MS: m/z 428.07 [M+H]⁺; HPLC Purity:97.7%.

Example 205-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(20)

2-((1-(4-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile (CO)

To a stirred solution of 1-(4-fluorophenyl)ethan-1-amine (CN, 0.5 g,3.59 mmol) in ethanol (10 mL), 2-chloropyrimidine-5-carbonitrile (AF,0.55 g, 3.95 mmol) and DIPEA (3.0 mL, 17.9 mmol) were added and thereaction mixture was heated to 90° C. for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20%EtOAc/hexane to afford compound CO (0.8 g, 91%) as a white solid. LC-MS:m/z 243.1 [M+H]⁺.

N-(1-(4-fluorophenyl)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (CP)

To a stirred solution of compound CO (0.8 g, 3.30 mmol) in DMF (10 mL),NaN₃ (0.89 g, 16.5 mmol), NH₄Cl (1.0 g, 16.5 mmol) and LiCl (240 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjusted to pH=4-5 by usingaqueous HCl solution. The obtained solid was filtered, washed withwater, dried to afford compound CP (0.8 g, crude) as a thick oil. LC-MS:m/z 286.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(20)

To a stirred solution of compound CP (0.4 g, 1.4 mmol) in DCM (10 mL),2,2-difluoroacetic anhydride (1.5 mL, 6.78 mmol) was added at 0° C. Thereaction mixture was stirred at RT for 30 min and then stirred at 90° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 80% EtOAc/hexane to afford compound 20 (0.1 g, 21%)as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (dd, J=11.0, 8.0Hz, 3H), 7.50 (t, J=51.4 Hz, 1H), 7.40-7.39 (m, 2H), 7.12 (t, J=8.8 Hz,2H), 5.20 (t, J=7.6 Hz, 1H), 1.45 (d, J=6.8 Hz, 3H); LC-MS: m/z 336[M+H]⁺; HPLC Purity: 99.8%.

Example 215-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methoxyethyl)pyrimidin-2-amine(21)

1-(4-fluorophenyl)-2-methoxyethan-1-one (CR)

To a stirred solution of 1-(4-fluorophenyl)ethan-1-one (CQ, 4.0 g, 28.0mmol) and tetrabutyl ammonium iodide (TBAI, 2.14 g, 5.79 mmol) in MeOH(75 mL), TsNHNH₂ (5.2 g, 28.0 mmol) and tert-butyl hydroperoxide (TBHP,70%, 21.6 mL, 168 mmol) were added and the reaction mixture was stirredat RT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched usingsaturated aqueous Na₂S₂O₃ solution and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 8% EtOAc/hexane toafford compound CR (2.5 g, 52%) as a thick oil. LC-MS: m/z 169 [M+H]⁺.

1-(4-fluorophenyl)-2-methoxyethan-1-amine (CS)

To a stirred solution of compound CR (1.2 g, 7.14 mmol) in MeOH (15 mL),NH₄OAc (5.5 g, 71.4 mmol) was added and the reaction mixture was stirredat RT for 2 h. NaCNBH₃ (0.9 g, 74.2 mmol) was added and the reactionmixture was stirred at RT for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was diluted with 1NHCl solution to pH=1 and extracted with EtOAc. The aqueous layer wasbasified with 10% NaOH solution to pH=10 and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound CS(0.68 g, 56.6%) as a thick oil. LC-MS: m/z 170.1 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-methoxyethyl)amino)pyrimidine-5-carbonitrile(CT)

To a stirred solution of compound CS (0.5 g, 2.95 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.45 g, 3.25 mmol) and DIPEA(2.52 mL, 14.7 mmol) were added and the reaction mixture was heated to90° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound CT (0.61g, 76%) as a white solid. LC-MS: m/z 272.05 [M+H]⁺.

N-(1-(4-fluorophenyl)-2-methoxyethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(CU)

To a stirred solution of compound CT (0.6 g, 2.20 mmol) in DMF (10 mL),NaN₃ (0.71 g, 11.0 mmol), NH₄Cl (0.6 g, 11.0 mmol) and LiCl (90 mg) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered and washed with water,dried to afford compound CU (0.65 g, crude) as an off white solid.LC-MS: m/z 316.2 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methoxyethyl)pyrimidin-2-amine(21)

To a stirred solution of compound CU6 (0.31 g, 2.06 mmol) in DCM (10mL), 2,2-difluoroacetic anhydride (0.34 mL, 3.90 mmol) was added. Thereaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 50%EtOAc/hexane to afford compound 21 (0.1 g, 13.5%) as a colorless stickysolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J=12.8 Hz, 2H), 8.80 (d,J=8.8 Hz, 1H), 7.51 (t, J=51.2 Hz, 1H), 7.47-7.45 (m, 2H), 7.16 (t,J=8.8 Hz, 2H), 5.36-5.33 (m, 1H), 3.65 (t, J=9.4 Hz, 1H), 3.54-3.51 (m,1H), 3.28 (s, 3H); LC-MS: m/z 366.1 [M−H]; HPLC Purity: 99.6%.

Example 225-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)propyl)pyrimidin-2-amine(22)

1-(4-fluorophenyl)propan-1-one (CW)

To a solution of anhydrous AlCl₃ (13.8 g, 104 mmol) in DCM (10 mL) at 0°C., a solution of propionyl chloride (6.8 mL, 78.1 mmol) in DCM (25 mL)was added drop wise and the reaction mixture was stirred at RT for 1 h.To this a solution, fluorobenzene (CV, 5.0 g, 52.0 mmol) in DCM (15 mL)was added drop wise and the reaction mixture was stirred at RT for 12 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was quenched with water and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using 5% EtOAc/hexane toafford compound CW (4.0 g, 50%) as an off white solid LC-MS: m/z 153.05[M+H]⁺.

1-(4-fluorophenyl)propan-1-amine (CX)

To a stirred solution of compound CW (4.0 g, 26.3 mmol) in MeOH (50 mL),ammonium acetate (20.2 g, 263 mmol) was added and the reaction mixturewas stirred at RT for 30 min. NaCNBH₃ (3.30 g, 52.6 mmol) was added andthe reaction mixture was stirred at RT for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with 1N HCl solution and extracted withEtOAc. The aqueous layer basified with 10% NaOH solution and extractedwith 10% MeOH/DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford compound CX (2.0 g, 49.7%) as a thick oil. LC-MS: m/z 154 [M+H]⁺.

2-((1-(4-fluorophenyl) propyl) amino) pyrimidine-5-carbonitrile (CY)

To a stirred solution of compound CX (0.55 g, 3.59 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.50 g, 3.59 mmol) and DIPEA(1.94 mL, 10.7 mmol) were added and the reaction mixture was heated to90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound CY (0.8 g,87%) as an off white solid. LC-MS: m/z 257.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.81 (d, J=7.6 Hz, 1H), 8.61 (s, 2H), 7.38-7.34 (m, 2H),7.14-7.04 (m, 2H), 4.90-4.85 (m, 1H), 2.29-1.46 (m, 2H), 0.83-0.78 (m,3H).

N-(1-(4-fluorophenyl)propyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (CZ)

To a stirred solution of compound CY (0.5 g, 1.95 mmol) in DMF (10 mL),NaN₃ (0.38 g, 5.85 mmol), NH₄Cl (0.31 g, 5.85 mmol) and LiCl (82 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered, washed with water, driedto afford compound CZ (0.3 g, crude) as a thick oil. LC-MS: m/z 300.1[M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)propyl)pyrimidin-2-amine(22)

To a stirred solution of compound CZ (0.3 g, 1.0 mmol) in DCM (10 mL),2,2-difluoroacetic anhydride (0.16 mL) was added at 0° C. The reactionmixture was stirred at RT for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 5% MeOH/DCM to afford compound22 (0.11 g, 31.4%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.83 (d, J=12.4 Hz, 2H), 8.77 (d, J=8.8 Hz, 1H), 7.51 (t, J=51.4 Hz,1H), 7.44-7.38 (m, 2H), 7.13 (t, J=8.8 Hz, 2H), 5.01-4.95 (m, 1H),1.88-1.72 (m, 2H), 0.88 (t, J=7.2 Hz, 3H); LC-MS: m/z 350.06 [M+H]⁺;HPLC Purity: 99.8%.

Example 235-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)butyl)pyrimidin-2-amine(23)

1-(4-fluorophenyl)butan-1-one (DA)

To a solution of anhydrous AlCl₃ (13.8 g, 104 mmol) in DCM (10 mL) at 0°C. was added solution of butyryl chloride (7.0 mL, 78.1 mmol) in DCM (25mL) and the reaction mixture was stirred at RT for 1 h. To this asolution of fluorobenzene (CV, 5.0 g, 52.0 mmol) in DCM (15 mL) wasadded drop wise and the reaction mixture was stirred at RT for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with water and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using 5% EtOAc/hexane toafford compound DA (3.5 g, 40.6%) as an off white solid LC-MS: m/z167.01 [M+H]⁺.

1-(4-fluorophenyl)butan-1-amine (DB)

To a stirred solution of compound DA (3.0 g, 18.0 mmol) in MeOH (30 mL),ammonium acetate (13.9 g, 180 mmol) was added and the reaction mixturewas stirred at RT for 30 min. NaCNBH₃ (2.26 g, 36.1 mmol) was added andthe reaction mixture was stirred at RT for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with 1N HCl solution and extracted withEtOAc. The aqueous layer was basified with 10% NaOH solution andextracted with 10% MeOH/DCM. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford compound DB (1.5 g, 50%) as a thick oil. LC-MS: m/z168.15 [M+H]⁺.

2-((1-(4-fluorophenyl)butyl)amino)pyrimidine-5-carbonitrile (DC)

To a stirred solution of compound DB (0.5 g, 3.0 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.46 g, 3.31 mmol) and DIPEA(2.5 mL, 15.0 mmol) were added and the reaction mixture was heated to90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound DC (0.8g, 98%) as an off white solid. LC-MS: m/z 271.05 [M+H]⁺.

N-(1-(4-fluorophenyl)butyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (DD)

To a stirred solution of compound DC (0.8 g, 2.96 mmol) in DMF (10 mL),NaN₃ (0.8 g, 14.8 mmol), NH₄Cl (0.95 g, 14.8 mmol) and LiCl (240 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered, washed with water, driedto afford compound DD (0.51 g, crude) as a thick oil. LC-MS: m/z 314.05[M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)butyl)pyrimidin-2-amine(23)

To a stirred solution of compound DD (0.5 g, 1.59 mmol) in DCM (10 mL),2,2-difluoroacetic anhydride (2.0 mL) was added at 0° C. The reactionmixture was stirred at RT for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 60% EtOAc/hexane to affordcompound 23 (0.085 g, 14%) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.83 (d, J=9.2 Hz, 2H), 8.87 (d, J=8.8 Hz, 1H), 7.51 (t,J=51.4 Hz, 1H), 7.44-7.39 (m, 2H), 7.13 (t, J=8.8 Hz, 2H), 5.11-5.05 (m,1H), 1.87-1.79 (m, 1H), 1.71-1.64 (m, 1H), 1.41-1.23 (m, 2H), 0.89-0.86(m, 3H), LC-MS: m/z 364.17 [M+H]⁺; HPLC Purity: 98.3%.

Example 245-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine(24)

1-(4-fluorophenyl)butan-1-one (DE)

To the solution of anhydrous AlCl₃ (13.8 g, 104 mmol) in DCM (10 mL) at0° C., was added drop wise a solution of isobutyryl chloride (8.5 mL,78.1 mmol) in DCM (25 mL) and the reaction mixture was stirred at RT for1 h. To this a reaction mixture, a solution of fluorobenzene (CV, 5.0 g,52.0 mmol) in DCM (15 mL) was added drop wise and stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with water andextracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by column chromatography using 5%EtOAc/hexane to afford compound DE (3.5 g, 40%) as an off white solid.LC-MS: m/z 166.96 [M+H]⁺.

1-(4-fluorophenyl)-2-methylpropan-1-amine (DF)

To a stirred solution of compound DE (3.0 g, 18.0 mmol) in MeOH (30 mL),ammonium acetate (14.0 g, 180 mmol) was added and the reaction mixturewas stirred at RT for 30 min. Sodium cyano borohydride (2.26 g, 36.1mmol) was added and the reaction mixture was stirred at RT for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was diluted with 1N HCl solution andextracted with EtOAc. The aqueous layer basified with 10% NaOH solutionand extracted with 10% MeOH/DCM. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford compound DF (1.0 g, 33%) as a thick oil. LC-MS: m/z168.05 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-methylpropyl)amino)pyrimidine-5-carbonitrile(DG)

To a stirred solution of compound DF (0.5 g, 3.0 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.46 g, 3.31 mmol) and DIPEA(2.5 mL, 15.0 mmol) were added and the reaction mixture was heated to90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound DG (0.8g, 98%) as an off white solid. LC-MS: m/z 270.95 [M+H]⁺.

N-(1-(4-fluorophenyl)-2-methylpropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(DH)

To a stirred solution of compound DG (0.8 g, 2.96 mmol) in DMF (10 mL),NaN₃ (0.8 g, 14.8 mmol), NH₄Cl (0.95 g, 14.8 mmol) and LiCl (240 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtain solid was filtered, washed with water, anddried to afford compound DH (0.5 g, crude) as a thick oil. LC-MS: m/z314.11 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine(24)

To a stirred solution of compound DH (0.5 g, 1.59 mmol) in DCM (10 mL),2,2-difluoroacetic anhydride (2.0 mL) was added at 0° C. Reactionmixture was stirred at RT for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 60% EtOAc/hexane to affordcompound 24 (0.33 g, 57%) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.84-8.79 (m, 3H), 7.51 (t, J=51.4 Hz, 1H), 7.45-7.41 (m,2H), 7.13 (t, J=8.8 Hz, 2H), 4.79 (t, J=9.2 Hz, 1H), 2.11-2.05 (m, 1H),1.0 (d, J=6.4 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H) LC-MS: m/z 364 [M+H]⁺;HPLC Purity: 99.4%.

Example 255-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl) picolinonitrile (25)

1-(6-bromopyridin-3-yl)cyclopropan-1-amine (DJ)

To a stirred solution of 6-bromonicotinonitrile (DI, 1 g, 5.46 mmol) indiethyl ether (30 mL), ethyl magnesium bromide (3M in THF, 4 mL, 12.02mmol) and titanium isopropoxide (1.70 g, 6.00 mmol) were added at −78°C. and the reaction mixture was stirred at RT for 2 h. BF₃.OEt₂ (1.53 g,10.92 mmol) was added at 0° C. and stirred at RT for 14 h. The progressof the reaction was monitored by TLC. After completion of the reaction,the reaction mixture was quenched with aqueous saturated NH₄Cl solution,basified with 10% NaOH solution and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 5% MeOH/DCM to affordcompound DJ (0.6 g, 51.7%) as a brown liquid. LC-MS: m/z 215.09[M+H+2]⁺.

2-((1-(6-bromopyridin-3-yl)cyclopropyl)amino)pyrimidine-5-carbonitrile(DK)

To a stirred solution of compound DJ (0.6 g, 2.81 mmol) in ethanol (20mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.51 g, 3.66 mmol) and DIPEA(2.45 mL, 14.05 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound DK (0.4g, 44.9%) as a brown liquid. LC-MS: m/z 315.95 [M+H]⁺.

N-(1-(6-bromopyridin-3-yl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(DL)

To a stirred solution of compound DK (0.3 g, 0.948 mmol) in DMF (5 mL),NaN₃ (0.185 g, 2.84 mmol), NH₄Cl (0.152 g, 2.84 mmol) and LiCl (30 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound DL(0.3 g, crude) as an off white solid. LC-MS: m/z 358.98 [M+H]⁺.

N-(1-(6-bromopyridin-3-yl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(66)

To a stirred solution of compound DL (0.3 g, 0.835 mmol) in DCM (10 mL),DFAA (1 mL) was added and the reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in saturated solution of NaHCO₃ andextracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 20%EtOAc/hexane to afford compound 66 (0.09 g, 26.3%) as an off whitesolid. LC-MS: m/z 409.05 [M+H]⁺.

5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile(25)

A stirred solution of compound 66 (0.08 g, 0.195 mmol) and Zn(CN)₂(0.034 g, 0.293 mmol) in DMF (2 mL) was purged with argon for 20 min andthen Pd(PPh₃)₄(0.022 g, 0.019 mmol) was added. The reaction mixture wasfurther purged with argon for 20 min and stirred at 150° C. for 5 h.After completion of the reaction, the reaction mixture was quenched withice water, filtered through Celite and washed with EtOAc. The filtratewas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 40% EtOAc/hexane to afford 25 (0.04 g,51.7%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H),8.94 (s, 1H), 8.87 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.4 Hz,1H), 7.76-7.74 (m, 1H), 7.53 (t, J=51.4 Hz, 1H), 1.56-1.55 (m, 2H),1.45-1.42 (m, 2H), LC-MS: m/z 356.05 [M+H]⁺; HPLC Purity: 99.2%.

Example 261-(4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-(4-fluorophenyl)piperidin-1-yl) ethan-1-one (26)

tert-butyl 4-cyano-4-(4-fluorophenyl)piperidine-1-carboxylate (DN)

To a stirred solution of 2-(4-fluorophenyl)acetonitrile (3.2 g, 23.7mmol) and tert-butyl bis(2-chloroethyl)carbamate (DM, 6.69 g, 23.7 mmol)in DMF (40 mL), NaH (60%, 2.8 g, 71.1 mmol) was added and the reactionmixture was stirred at 60° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched using water and extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 10% EtOAc/hexane to affordcompound DN (4.2 g, 58%) as a thick oil.

4-(4-fluorophenyl)piperidine-4-carbonitrile (DO)

To a stirred solution of compound DN (4.2 g, 5.50 mmol) in EtOAc (5 mL),4M HCl in EtOAc (10 mL) was added at 0° C. and stirred at RT for 2 h Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressureto afford compound DO (30 g, crude) as a white solid. LC-MS: m/z 204.95[M+H]⁺.

1-acetyl-4-(4-fluorophenyl)piperidine-4-carbonitrile (DP)

To a stirred solution of compound DO (3.0 g, 14.6 mmol) in DCM (30 mL),acetic acid (2.9 mL, 29.3 mmol) was added at 0° C. and the reactionmixture was stirred at RT for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby column chromatography using 5% MeOH/DCM to afford compound DP (2.8 g,77%) as a white solid. LC-MS: m/z 247 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 11.9 (s, 1H), 7.62-7.57 (m, 2H), 7.31-7.25 (m, 2H), 4.59-4.56 (m, 1H),4.02-3.98 (m, 1H), 3.33-3.26 (m, 1H), 2.81-2.74 (m, 1H), 2.16-2.01 (m,4H), 1.90-1.81 (m, 2H).

1-acetyl-4-(4-fluorophenyl)piperidine-4-carboxamide (DQ)

To a stirred solution of compound DP (2.8 g, 11.3 mmol) in DMSO (30 mL),K₂CO₃ (6.3 g, 45.5 mmol) and H₂O₂(30%, 5.1 mL, 45.5 mmol) were added andthe reaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with ice-water and the obtained solid wasfiltered and dried. The crude product was purified by columnchromatography using 5% MeOH/DCM to afford compound DQ (2.8 g, 93%) as awhite solid. LC-MS: m/z 265.04 [M+H]⁺.

1-(4-amino-4-(4-fluorophenyl)piperidin-1-yl)ethan-1-one (DR)

To a stirred solution of compound DQ (2.6 g, 9.84 mmol) in ACN:Water(1:1, 30 mL), PhI(CF₃COO)₂ (5.0 g, 11.8 mmol) was added and the reactionmixture was stirred at 60° C. for 7 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water and extracted with 10% MeOH/DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 5% MeOH/DCM to afford compound DR(0.67 g, 29%) as a thick oil. LC-MS: m/z 220.1 [M+H]⁺.

2-((1-acetyl-4-(4-fluorophenyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(DS)

To a stirred solution of compound DR (0.4 g, 2.86 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.67 g, 2.86 mmol) and DIPEA(2.6 mL, 14.3 mmol) were added and the reaction mixture was heated to90° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 50% EtOAc/hexane to afford compound DS (0.4g, 41%) as a white solid. LC-MS: m/z 341.1 [M+H]⁺.

1-(4-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-4-(4-fluorophenyl)piperidin-1-yl)ethan-1-one(DT)

To a stirred solution of compound DS (0.4 g, 1.17 mmol) in DMF (10 mL),NaN₃ (0.31 g, 5.8 mmol), NH₄Cl (0.37 g, 5.88 mmol) and LiCl (120 mg)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound DT(0.27 g, crude) as a thick oil. LC-MS: m/z 383.10 [M+H]⁺.

1-(4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-(4-fluorophenyl)piperidin-1-yl)ethan-1-one (26)

To a stirred solution of compound DT (0.26 g, 0.69 mmol) in DCM (15 mL),2,2-difluoroacetic anhydride (0.12 mL, 1.04 mmol) was added at 0° C. andthe reaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 6%MeOH/DCM to afford compound 26 (0.04 g, 13%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.63 (s, 2H), 7.47 (t, J=51.2 Hz,1H), 7.41-7.38 (m, 2H), 7.07 (t, J=9.2 Hz, 2H), 4.25 (d, J=13.2 Hz, 1H),2.83 (t, J=12.4 Hz, 1H), 2.63-2.59 (m, 3H), 1.98 (s, 3H), 1.93-1.90 (m,1H), 1.80-1.74 (m, 1H); LC-MS: m/z 431 [M−H]; HPLC Purity: 95.1%.

Example 27N-(1-cyclohexylcyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(27)

1-cyclohexylcyclopropan-1-amine (DV)

To a stirred solution of cyclohexanecarbonitrile (DU, 1.50 g, 13.74mmol) in diethyl ether (80 mL), ethyl magnesium bromide (3M in THF,11.45 mL, 34.35 mmol) and titanium isopropoxide (4.29 g, 15.11 mmol)were added at −78° C. and the reaction mixture was stirred at RT for 2h. BF₃.OEt₂ (3.89 g, 27.48 mmol) was added at 0° C. and stirred at RTfor 14 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with NH₄Clsolution, basified with 10% NaOH solution, and extracted with 10%MeOH/DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound DV (0.6 g, 31.4%) as a brown liquid.LC-MS: m/z 140.0 [M+H]⁺.

2-((1-cyclohexylcyclopropyl)amino)pyrimidine-5-carbonitrile (DX)

To a stirred solution of compound DV (0.4 g, 2.87 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.44 g, 3.16 mmol) and DIPEA(2.50 mL, 14.35 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 10% EtOAc/hexane to afford compound DX (0.55g, 79%) as a white solid. LC-MS: m/z 243.0 [M+H]⁺.

N-(1-cyclohexylcyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (DY)

To a stirred solution of compound DX (0.5 g, 2.06 mmol) in DMF (10 mL),NaN₃ (0.66 g, 10.3 mmol), NH₄Cl (0.55 g, 10.3 mmol) and LiCl (100 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was suspended in water and the obtained solid was filtered,washed with water, and dried to afford compound DY (0.43 g, crude) as ayellow solid. LC-MS: m/z 286.08 [M+H]⁺.

N-(1-cyclohexylcyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(27)

To a stirred solution of compound DY (0.4 g, 1.40 mmol) in DCM (10 mL),DFAA (2 mL) was added and the reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in a saturated solution of NaHCO₃and extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 50% EtOAc/hexane to afford compound 27 (0.024 g,5%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J=3.2Hz, 2H), 8.78 (d, J=2.8 Hz, 1H), 8.50 (s, 1H), 7.51 (t, J=51.4 Hz, 1H),1.75 (d, J=11.6 Hz, 2H), 1.65 (d, J=12.0 Hz, 2H), 1.56 (d, J=11.6 Hz,1H), 1.43 (t, J=12.0 Hz, 1H), 1.16-0.99 (m, 3H), 0.93-0.85 (m, 2H),0.76-0.73 (m, 1H), 0.64-0.61 (m, 2H), LC-MS: m/z 336.16 [M+H]⁺; HPLCPurity: 99.3%.

Example 285-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-isopropylcyclopropyl)pyrimidin-2-amine(28)

1-isopropylcyclopropan-1-amine (EA)

To a stirred solution of isobutyronitrile (DZ, 2 g, 28.9 mmol) indiethyl ether (40 mL), ethyl magnesium bromide (3M in THF, 21.25 mL,63.6 mmol) and titanium isopropoxide (9.04 g, 31.8 mmol) were added at−78° C. and the reaction mixture was stirred at RT for 2 h. BF₃.OEt₂(8.23 g, 57.8 mmol) was added at 0° C. and stirred at RT for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with NH₄Cl solution,basified with 10% NaOH solution, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 30% EtOAc/hexane toafford compound EA (0.8 g, 27.8%) as a brown liquid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.12 (br s, 2H), 1.58-1.45 (m, 2H), 0.95-0.88 (m, 4H),0.72-0.63 (m, 5H).

2-((1-isopropylcyclopropyl)amino)pyrimidine-5-carbonitrile (EB)

To a stirred solution of compound EA (0.35 g, 3.52 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.49 g, 3.16 mmol) and DIPEA(1.84 mL, 10.5 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound EB (0.3g, 42%) as an off white solid. LC-MS: m/z 203.05 [M+H]⁺.

N-(1-isopropylcyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine (EC)

To a stirred solution of compound EB (0.3 g, 1.48 mmol) in DMF (5 mL),NaN₃ (0.28 g, 4.44 mmol), NH₄Cl (0.24 g, 4.44 mmol) and LiCl (50 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound EC(0.3 g, crude) as a light yellow solid. LC-MS: m/z 245.95 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-isopropylcyclopropyl)pyrimidin-2-amine(28)

To a stirred solution of compound EC (0.3 g, 1.22 mmol) in DCM (5 mL),DFAA (0.5 mL) was added and the reaction mixture was stirred at RT for12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in saturated solution ofNaHCO₃ and extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 30% EtOAc/hexane to afford compound 28 (0.06 g,16.6%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H),8.81 (s, 1H), 8.50 (s, 1H), 7.51 (t, J=51.4 Hz, 1H), 1.89-1.83 (m, 1H),0.86 (d, J=6.8 Hz, 6H), 0.76-0.67 (m, 2H), 0.66-0.64 (m, 2H); LC-MS: m/z296 [M+H]⁺; HPLC Purity: 99.8%.

Example 295-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine(29)

(Z)-5-fluoro-2,3-dihydro-1H-inden-1-one oxime (EE)

To a stirred solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (ED, 2 g,13.32 mmol) in EtOH (50 mL), aqueous NaOAc (2.73 g, 33.3 mmol) andNH₂OH.HCl (2.31 g, 33.3 mmol) were added and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was washed with waterand dried to afford compound EE (2 g, 90.9%) as a white solid. LC-MS:m/z 166 [M+H]⁺.

5-fluoro-2,3-dihydro-1H-inden-1-amine (EF)

To a stirred solution of compound EE (2 g, 11.1 mmol) in MeOH (50 mL),acetic acid (10 mL) and palladium on carbon (200 mg) were added andstirred under hydrogen balloon pressure at RT for 12 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through pad of celite and washed withMeOH. The filtrate was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 10%MeOH/DCM to afford compound EF (1.2 g, 65.5%) as a brown liquid. LC-MS:m/z 135.00 [M−16]⁺.

2-((5-fluoro-2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carbonitrile(EG)

To a stirred solution of compound EF (0.5 g, 3.30 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.69 g, 4.96 mmol) and DIPEA(2.72 mL, 9.90 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 15% EtOAc/hexane to afford compound EG (0.70g, 83.3%) as a white solid. LC-MS: m/z 254.95 [M+H]⁺.

N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(EH)

To a stirred solution of compound EG (0.6 g, 2.35 mmol) in DMF (10 mL),NaN₃ (0.76 g, 11.7 mmol), NH₄Cl (0.62 g, 11.5 mmol) and LiCl (180 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound EH(0.30 g, crude) as a yellow solid. LC-MS: m/z 297.95 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine(29)

To a stirred solution of compound EH (0.3 g, 1.00 mmol) in DCM (10 mL),DFAA (1 mL) was added and the reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in saturated solution of NaHCO₃ andextracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound 29 (0.03 g, 8.5%) as an off white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (d, J=21.2 Hz, 2H), 8.61 (d, J=8.4 Hz,1H), 7.53 (t, J=51.4 Hz, 1H), 7.24-7.21 (m, 1H), 7.10-7.08 (m, 1H),6.98-6.94 (m, 1H), 5.63-5.57 (m, 1H), 3.04-3.0 (m, 1H), 2.97-2.86 (m,1H), 2.07-1.99 (m, 1H); LC-MS: m/z 347.95 [M+H]⁺; HPLC Purity: 99.7%.

Example 302-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-1-morpholinoethan-1-one(30)

2-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)acetic acid (EJ)

To a stirred solution of 2-amino-2-(4-fluorophenyl)acetic acid (EI, 2.5g, 14.77 mmol) in THF (25 mL), boc anhydride (3.54 g, 16.25 mmol) andNaOH (3N, 20 mL) were added and stirred at room temperature for 12 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, reaction mixture was quenched with 6N HCl solution andextracted with EtOAc. The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to affordcompound EJ (2.2 g, crude) as a brown oil. LC-MS: m/z 269.23 [M+H]⁺.

tert-butyl(1-(4-fluorophenyl)-2-morpholino-2-oxoethyl)carbamate (EK)

To a stirred solution of compound EJ (1 g, 3.71 mmol) in DCM (15 mL),morpholine (0.35 g, 4.08 mmol), HATU (1.69 g, 4.45 mmol) and DIPEA (1.90mL, 11.13 mmol) were added at 0° C. under nitrogen atmosphere andstirred at room temperature for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water and extracted with EtOAc. The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 5% MeOH/DCM to afford compound EK (1.1 g, 88%) asan off white solid. LC-MS: m/z 239.07 [M+H−100]⁺.

2-amino-2-(4-fluorophenyl)-1-morpholinoethan-1-one (EL)

To a stirred solution of compound EK (1.1 g, 3.25 mmol) in DCM (12 mL),TFA (1 mL) was added and the reaction mixture was stirred at roomtemperature for 2 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure to obtain compound as a TFA salt. The salt wasbasified with NaHCO₃ solution and extracted with 15% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 5% MeOH/DCM to affordcompound EL (0.6 g, 77.9%) as an off white solid. LC-MS: m/z 238.94[M+H]⁺.

2-((1-(4-fluorophenyl)-2-morpholino-2-oxoethyl)amino)pyrimidine-5-carbonitrile(EM)

To a stirred solution of compound EL (0.6 g, 2.51 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.45 g, 3.26 mmol) and DIPEA(2.19 mL, 12.55 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound EM (0.55 g,64%) as a brown liquid. LC-MS: m/z 342.0 [M+H]⁺.

2-((5-(H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-1-morpholinoethan-1-one(EN)

To a stirred solution of compound EM (0.55 g, 1.61 mmol) in DMF (10 mL),NaN₃ (0.314 g, 4.83 mmol), NH₄Cl (0.258 g, 4.83 mmol) and LiCl (50 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was washed with water and dried to afford compound EN (0.30g, crude) as an off white solid. LC-MS: m/z 385.0 [M+H]⁺.

2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-1-morpholinoethan-1-one(30)

To a stirred solution of compound EN (0.3 g, 0.780 mmol) in DCM (10 mL),DFAA (0.20 g, 1.15 mmol) was added and the reaction mixture was stirredat RT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in saturated solution ofNaHCO₃ and extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 50% EtOAc/hexane to afford compound 30 (0.107 g,31.5%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (d, J=2.0Hz, 2H), 8.55 (d, J=7.2 Hz, 1H), 7.58-7.53 (m, 2H), 7.55 (t, J=51.2 Hz,1H), 7.21 (t, J=8.8 Hz, 2H), 6.10 (d, J=7.2 Hz, 1H), 3.54-3.47 (m, 7H),3.21-3.19 (m, 1H); LC-MS: m/z 435.05 [M+H]⁺; HPLC Purity: 99.1%.

Example 315-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)ethyl)pyrimidin-2-amine(31)

1-(5-fluoropyridin-2-yl)ethan-1-one (EP)

To a stirred solution of 5-fluoropicolinonitrile (EO, 2.9 g, 23.75 mmol)in THF (20 mL), methyl magnesium bromide (3M in THF, 10.2 mL, 30.87mmol) was added at −65° C. and stirred for 1.5 h. The reaction mixturewas further stirred at RT for 3 h. 2M HCl (10 mL) was added and thereaction mixture was further stirred at RT for 14 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with saturated aqueous NaHCO₃ solution andextracted with DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 15%EtOAc/hexane to afford compound EP (1.8 g, 54.5%) as a colorless liquid.LC-MS: m/z 140.00 [M+H]⁺.

(E)-1-(5-fluoropyridin-2-yl)ethan-1-one oxime (EQ)

To a stirred solution of compound EP (1.8 g, 12.9 mmol) in EtOH (20 mL),triethyl amine (3.38 mL, 19.4 mmol) and NH₂OH.HCl (1.3 g, 19.4 mmol)were added and the reaction mixture was stirred at RT for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 25% EtOAc/hexane toafford EQ (1.8 g, 94.7%) as an off white solid. LC-MS: m/z 154.84[M+H]⁺.

1-(5-fluoropyridin-2-yl)ethan-1-amine (ER)

To a stirred solution of compound EQ (1.8 g, 11.6 mmol) in H₂O (25 mL),NH₄OH (4 g, 116 mmol), NH₄OAc (1.07 g, 13.9 mmol) and zinc dust (3.08 g,46.4 mmol) were added and the reaction mixture was heated to 50° C. for3 h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with aqueous NaClsolution and EtOAc and the resulting solution was stirred for 1 h atroom temperature. The resulting mixture was filtered through pad ofcelite and washed with EtOAc. The combined filtrate was washed with 2.5%NaOH solution, brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 5% MeOH/DCM to afford ER (1 g, 62.5%) as a brownliquid. LC-MS: m/z 140.99 [M+H]⁺.

2-((1-(5-fluoropyridin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (ES)

To a stirred solution of compound ER (0.5 g, 3.56 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.74 g, 5.35 mmol) and DIPEA(1.86 mL, 10.7 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 15% EtOAc/hexane to afford compound ES (0.70g, 80.7%) as an off white solid. LC-MS: m/z 243.90 [M+H]⁺.

N-(1-(5-fluoropyridin-2-yl)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin -2-amine(ET)

To a stirred solution of compound ES (0.7 g, 2.87 mmol) in DMF (10 mL),NaN₃ (0.92 g, 14.3 mmol), NH₄Cl (0.767 g, 14.3 mmol) and LiCl (210 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was suspended in water and the obtained solid was filtered,washed with water and dried to afford compound ET (0.6 g, crude) as anoff white solid. LC-MS: m/z 287.00 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)ethyl)pyrimidin-2-amine(31)

To a stirred solution of compound ET (0.6 g, 2.09 mmol) in DCM (10 mL),DFAA (0.79 g, 4.19 mmol) was added and the reaction mixture was stirredat RT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in aqueous saturatedsolution of NaHCO₃ and extracted with EtOAc. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 50% EtOAc/hexane to afford compound 31 (0.1g, 14%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d,J=4.0 Hz, 2H), 8.71 (d, J=7.2 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 7.71-7.62(m, 1H), 7.51 (t, J=51.4 Hz, 1H), 7.48-7.43 (m, 1H), 5.30-5.25 (m, 1H),1.38 (d, J=6.8 Hz, 3H); LC-MS: m/z 337 [M+H]⁺; HPLC Purity: 99.7%.

Example 32N-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(32)

4-(difluoromethoxy)benzonitrile (EV)

To a stirred solution of 4-hydroxybenzonitrile (EU, 5 g, 41.97 mmol) inDMF (50 mL), NaOH (2.01 g, 50.36 mmol) and sodium chlorodifluoro acetate(7.67 g, 50.36 mmol) were added and the reaction mixture was stirred at125° C. for 8 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was quenched withwater and extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 5% MeOH/DCM to afford compound EV (3.8 g, 53.5%) asan off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J=7.5 Hz, 2H),7.42 (t, J=52.4 Hz, 1H), 7.18-7.15 (m, 2H).

1-(4-(difluoromethoxy)phenyl)cyclopropan-1-amine (EW)

To a stirred solution of compound EV (4 g, 23.66 mmol) in diethyl ether(100 mL), ethyl magnesium bromide (3M in THF, 17.3 mL, 52.03 mmol) andtitanium isopropoxide (7.39 g, 26.02 mmol) were added at −78° C. and thereaction mixture was stirred at RT for 2 h. BF₃.OEt₂ (6.72 g, 47.32mmol) was added at 0° C. and the reaction mixture was stirred at RT for14 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with NH₄Clsolution, basified with 10% NaOH solution, and extracted with 10%MeOH/DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 5%MeOH/DCM to afford compound EW (1.5 g, 31.84%) as a brown liquid.

2-((1-(4-(difluoromethoxy)phenyl)cyclopropyl)amino)pyrimidine-5-carbonitrile(EX)

To a stirred solution of compound EW (0.71 g, 3.57 mmol) in ethanol (15mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.5 g, 3.57 mmol) and DIPEA(1.86 mL, 10.71 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound EX (0.5 g,46.3%) as an off white solid. LC-MS: m/z 302.99 [M+H]⁺.

N-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(EY)

To a stirred solution of compound EX (0.3 g, 0.992 mmol) in DMF (10 mL),NaN₃ (0.193 g, 2.97 mmol), NH₄Cl (0.159 g, 2.97 mmol) and LiCl (0.041 g,0.992 mmol) were added and the reaction mixture was stirred at 100° C.for 14 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in water and the obtainsolid was filtered. The solid was washed with water and dried to affordcompound EY (0.250 g, crude) as an off white solid. LC-MS: m/z 346.06[M+H]⁺.

N-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(32)

To a stirred solution of compound EY (0.25 g, 0.723 mmol) in DCM (10mL), DFAA (0.25 g, 1.44 mmol) was added and the reaction mixture wasstirred at RT for 12 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved insaturated solution of NaHCO₃ and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 5% MeOH/DCM to afford compound 32(0.06 g, 21%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.04(s, 1H), 8.87 (d, J=10.8 Hz, 2H), 7.51 (t, J=51.1 Hz, 1H), 7.24 (d,J=8.4 Hz, 2H), 7.14 (t, J=74.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H),1.33-1.25 (m, 4H); LC-MS: m/z 395.95 [M+H]⁺; HPLC Purity: 99.6%.

Example 33N-(1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(33)

1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropan-1-amine (FA)

To a stirred solution of 4-(difluoromethoxy)-2-fluorobenzonitrile (EZ, 1g, 5.34 mmol) in diethyl ether (30 mL), ethyl magnesium bromide (3M inTHF, 3.91 mL, 11.75 mmol) and titanium isopropoxide (1.67 g, 5.87 mmol)were added at −78° C. and the reaction mixture was stirred at RT for 2h. BF₃.OEt₂ (1.51 g, 10.68 mmol) was added at 0° C. and stirred at RTfor 14 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with NH₄Clsolution, basified with 10% NaOH solution, and extracted with 10%MeOH/DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 5%MeOH/DCM to afford compound FA (0.458 g, 39.4%) as a brown liquid.LC-MS: m/z 218.00 [M+H]⁺.

2-((1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)amino)pyrimidine-5-carbonitrile(FB)

To a stirred solution of compound FA (0.45 g, 2.07 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.34 g, 2.48 mmol) and DIPEA(1.44 mL, 8.28 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound FB (0.5 g,76.3%) as a white solid. LC-MS: m/z 320.95 [M+H]⁺.

N-(1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(FC)

To a stirred solution of compound FB (0.5 g, 1.56 mmol) in DMF (10 mL),NaN₃ (0.304 g, 4.68 mmol), NH₄Cl (0.252 g, 4.68 mmol) and LiCl (100 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in water and the obtained solid was filtered,washed with water, and dried to afford compound FC (0.4 g, crude) as abrown liquid. LC-MS: m/z 364.03 [M+H]⁺.

N-(1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(33)

To a stirred solution of compound FC (0.4 g, 1.10 mmol) in DCM (15 mL),DFAA (0.383 g, 2.20 mmol) was added and the reaction mixture was stirredat RT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in aqueous saturatedsolution of NaHCO₃ and extracted with EtOAc. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 50% EtOAc/hexane to afford compound 33 (0.08g, 17.5%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s,1H), 8.85 (d, J=17.6 Hz, 2H), 7.15-7.67 (m, 1H), 7.51 (t, J=51.2 Hz,1H), 7.23 (t, J=67.4 Hz, 1H), 7.02-7.01 (m, 1H), 6.95-6.93 (m, 1H),1.28-1.25 (m, 2H), 1.20-1.19 (m, 2H); LC-MS: m/z 413.95 [M+H]⁺; HPLCPurity: 99.5%.

Example 345-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidin-2-amine(34)

(Z)-6-fluoro-3,4-dihydronaphthalen-1 (2H)-one oxime (FE)

To a stirred solution of 6-fluoro-3,4-dihydronaphthalen-1(2H)-one (FD, 2g, 12.18 mmol) in ethanol (50 mL), aqueous NaOAc (2.49 g, 30.4 mmol) andNH₂OH.HCl (2.11 g, 30.4 mmol) were added and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was washed with waterand dried to afford compound FE (2 g, 95%) as a white solid. LC-MS: m/z179.90 [M+H]⁺.

6-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (FF)

To a stirred solution of compound FE (2 g, 11.1 mmol) in methanol (50mL), acetic acid (10 mL) and palladium on carbon (200 mg) were added andstirred under hydrogen balloon pressure at RT for 12 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through pad of celite and washed withmethanol. The filtrate was concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 10%MeOH/DCM to afford compound FF (1.2 g, 65%) as a brown liquid. LC-MS:m/z 148.85 [M−16]⁺.

2-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)amino)pyrimidine-5-carbonitrile(FG)

To a stirred solution of compound FF (0.5 g, 3.02 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.46 g, 3.32 mmol) and DIPEA(1.58 mL, 9.06 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20% EtOAc/hexane to afford compound FG (0.7g, 86%) as an off white solid. LC-MS: m/z 269.00 [M+H]⁺.

N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(FH)

To a stirred solution of compound FG (0.6 g, 2.23 mmol) in DMF (10 mL),NaN₃ (0.72 g, 11.1 mmol), NH₄Cl (0.59 g, 11.1 mmol) and LiCl (180 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound FH(0.5 g, crude) as an off white solid. LC-MS: m/z 312.0 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidin-2-amine(34)

To a stirred solution of compound FH (0.3 g, 0.96 mmol) in DCM (15 mL),DFAA (1 mL) was added and the reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in a saturated solution of NaHCO₃and extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford compound 34 (0.06 g,17%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=2.8Hz, 1H), 8.87 (d, J=3.2 Hz, 1H), 8.57 (d, J=8.8 Hz, 1H), 7.53 (t, J=51.4Hz, 1H), 7.23-7.19 (m, 1H), 6.97-6.92 (m, 2H), 5.32-5.28 (m, 1H),2.82-2.72 (m, 2H), 2.02-1.92 (m, 2H), 1.87-1.74 (m, 2H); LC-MS: m/z 362[M+H]⁺; HPLC Purity: 99.0%.

Example 352-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide(35)

2-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)acetic Acid (EJ)

To a stirred solution of 2-amino-2-(4-fluorophenyl)acetic acid (EI, 2.5g, 14.77 mmol) in THF (25 mL), boc anhydride (3.54 g, 16.25 mmol) andNaOH (3N, 20 mL) were added and stirred at room temperature for 12 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, reaction mixture was quenched with 6N HCl solution andextracted using EtOAc. The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to affordcompound EJ (2.2 g, crude) as a brown oil. LC-MS: m/z 170 [M+H−100]⁺.

tert-butyl(1-(4-fluorophenyl)-2-oxo-2-(phenylamino)ethyl)carbamate (FI)

To a stirred solution of compound EJ (1.1 g, 4.08 mmol) in DCM (25 mL),aniline (0.41 g, 4.49 mmol), HATU (1.86 g, 4.89 mmol) and DIPEA (2.13mL, 12.24 mmol) were added at 0° C. under nitrogen atmosphere and thereaction mixture was stirred at room temperature for 12 h. The progressof the reaction was monitored by TLC After completion, the reactionmixture was quenched with water and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound FI (1 g,71.42%) as an off white solid. LC-MS: m/z 289.07 [M−56]⁺.

2-amino-2-(4-fluorophenyl)-N-phenylacetamide (FJ)

To a stirred solution of compound FI (1 g, 2.90 mmol) in DCM (12 mL),TFA (0.8 mL) was added and the reaction mixture was stirred at roomtemperature for 2 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure to obtain the product as a TFA salt. The salt wasbasified with NaHCO₃ solution and extracted with 15% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude amine productwas purified by silica gel column chromatography using 5% MeOH/DCM toafford compound FJ (0.6 g, 84.6%) as an off white solid. LC-MS: m/z244.93 [M+H]⁺.

2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide(FK)

To a stirred solution of compound FJ (0.5 g, 2.04 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.42 g, 3.07 mmol) and DIPEA(1.78 mL, 10.2 mmol) were added and the reaction mixture was heated to90° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound FK (0.6 g,84.5%) as a brown liquid. LC-MS: m/z 347.95 [M+H]⁺.

2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide(FL)

To a stirred solution of compound FK (0.6 g, 1.72 mmol) in DMF (10 mL),NaN₃ (0.336 g, 5.18 mmol), NH₄Cl (0.277 g, 5.18 mmol) and LiCl (60 mg)were added and the reaction mixture was stirred at 100° C. for 14 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water and acidifiedwith 2N HCl solution to pH=2. The precipitated solid was filtered andwashed with cold water to afford compound FL (0.3 g, crude) as an offwhite solid. LC-MS: m/z 391.05 [M+H]⁺.

2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide(35)

To a stirred solution of compound FL (0.3 g, 0.768 mmol) in DCM (10 mL),DFAA (0.20 g, 1.15 mmol) was added and the reaction mixture was stirredat RT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in saturated solution ofNaHCO₃ and extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 50% EtOAc/hexane to afford compound 35 (0.007 g,2%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.4 (s, 1H),8.94 (d, J=8.0 Hz, 1H), 8.76 (d, J=7.6 Hz, 1H), 7.66-7.63 (m, 2H),7.59-7.57 (m, 2H), 7.40 (t, J=51.2 Hz, 1H), 7.31-7.22 (m, 4H), 7.04 (t,J=7.6 Hz, 1H), 5.90 (d, J=7.2 Hz, 1H), 1.23 (s, 1H). LC-MS: m/z 441.1[M+H]⁺; HPLC Purity: 92.2%.

Example 36N-(cyclopropyl(4-fluorophenyl)methyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(36)

(E)-cyclopropyl(4-fluorophenyl)methanone oxime (FN)

To a stirred solution of cyclopropyl(4-fluorophenyl)methanone (FM, 5 g,30.4 mmol) in EtOH (50 mL), triethyl amine (10.5 mL, 76.1 mmol) andNH₂OH.HCl (5.2 g, 76.1 mmol) were added and the reaction mixture wasstirred at 90° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was washed with waterand the solid dried to afford compound FN (5 g, 91.7%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.0 (s, 1H), 7.43-7.40 (m, 2H),7.25-7.16 (m, 2H), 0.89-0.85 (m, 2H), 0.76-0.73 (m, 1H), 0.51-0.47 (m,2H).

cyclopropyl(4-fluorophenyl)methanamine (FO)

To a stirred solution of compound FN (5 g, 27.9 mmol) in EtOH (50 mL),acetic acid (10 mL) and palladium on carbon (500 mg) were added andstirred under hydrogen balloon pressure at RT for 12 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through a pad of celite and washed withMeOH. The filtrate was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 10%MeOH/DCM to afford compound FO (4 g, 86.9%) as a brown liquid. LC-MS:m/z 166.05 [M+H]⁺.

2-((cyclopropyl(4-fluorophenyl)methyl)amino)pyrimidine-5-carbonitrile(FP)

To a stirred solution of compound FO (0.5 g, 3.02 mmol) in ethanol (10mL), 2-chloropyrimidine-5-carbonitrile (AF, 0.5 g, 3.63 mmol) and DIPEA(2.63 mL, 15.1 mmol) were added and the reaction mixture was heated to90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 30% EtOAc/hexane to afford compound FP (0.2g, 24.6%) as a pale yellow solid. LC-MS: m/z 269.03 [M+H]⁺.

N-(cyclopropyl(4-fluorophenyl)methyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(FQ)

To a stirred solution of compound FP (0.2 g, 0.74 mmol) in DMF (20 mL),NaN₃ (0.24 g, 3.72 mmol), NH₄Cl (0.19 g, 3.72 mmol) and LiCl (60 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingaqueous HCl solution. The obtained solid was filtered and dried toafford compound FQ (0.25 g, crude) as an off white solid. LC-MS: m/z312.0 [M+H]⁺.

N-(cyclopropyl(4-fluorophenyl)methyl)-N-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-2,2-difluoroacetamide(FR)

To a stirred solution of compound FQ (0.25 g, 0.80 mmol) in DCM (10 mL),DFAA (0.5 mL) was added at 0° C. The reaction mixture was stirred at RTfor 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 10% MeOH/DCM to afford compound FR (0.1 g, 28.4%)as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (s, 2H),7.56-7.51 (m, 2H), 7.49 (t, J=51.2 Hz, 1H), 7.14-7.10 (m, 1H), 6.92 (t,J=52.4 Hz, 1H), 5.30 (d, J=10 Hz, 1H), 1.96 (br s, 1H), 0.80 (s, 1H),0.46-0.45 (m, 2H), 0.22-0.21 (m, 2H).

N-(cyclopropyl(4-fluorophenyl)methyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(36)

To a stirred solution of compound FR (0.1 g, 0.22 mmol) in ACN (2 mL),K₂CO₃ (0.09 g, 0.68 mmol) was added and the reaction mixture was heatedto 80° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was filteredthrough a pad of celite and washed with EtOAC. The filtrate wasconcentrated under reduced pressure. The crude product was diluted withEtOAC and washed with water. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford 36 (0.03 g, 36%) as anoff white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=8.8 Hz, 1H),8.56 (br s, 1H), 8.76 (br s, 1H), 7.51 (t, J=51.2 Hz, 1H), 7.49-7.47 (m,2H), 7.14 (t, J=8.8 Hz, 2H), 4.40 (t, J=8.8 Hz, 1H), 1.32-1.28 (m, 1H),0.55-0.51 (m, 2H), 0.42-0.40 (m, 2H). LC-MS: m/z 362.1 [M+H]⁺; HPLCPurity: 95.9%.

Example 37N-(4,4-difluoro-1-(4-fluorophenyl)cyclohexyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(37)

2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide(FT)

To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (FS, 9 g, 57.62mmol) in DCE (150 mL), Ti(OEt)₄ (39.4 g, 172.8 mmol) and2-methylpropane-2-sulfinamide (15.3 g, 126.7 mmol) were added at 0° C.and the reaction mixture stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with saturated aqueous NaHCO₃ solution.The obtained solid was filtered and filtrate was extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 50% EtOAc/hexane toafford compound FT (10 g, 67%) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 3.94 (s, 1H), 3.02 (s, 4H),), 2.98-2.91 (m, 1H), 2.79-2.72(m, 1H), 2.35 (t, J=6.8 Hz, 1H), 1.94-1.78 (m, 4H), 1.12 (s, 9H), 1.07(s, 1H).

N-(8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-2-methylpropane-2-sulfinamide(FU)

To a stirred solution of compound FT (6 g, 23.13 mmol) in THF (60 mL)was added 1 M solution of (4-fluorophenyl)magnesium bromide in THF (60mL) and the reaction was stirred at 0° C. for 3 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with aqueous NH₄Cl solution and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 70%EtOAc/hexane to afford compound FU (5.9 g, 71.95%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.56-7.52 (m, 2H), 7.11 (t, J=8.8 Hz,2H), 5.21 (s, 1H), 3.86-3.83 (m, 4H), 2.22-2.08 (m, 4H), 1.19-1.80 (m,2H), 1.49-1.45 (m, 2H), 1.12-1.08 (s, 9H).

4-amino-4-(4-fluorophenyl)cyclohexan-1-one (FV)

To a stirred solution of compound FU (5.9 g, 16.59 mmol) in THF (30 mL),2M HCl (30 mL) was added and stirred reaction mixture at 50° C. for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The reaction residue was quenched with aqueous NaOH solutionand extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was dissolved in EtOAc, filtered, concentrated anddried to afford compound FV (2.4 g, crude) as an off white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.86 (s, 2H), 7.80-7.76 (m, 2H), 7.32 (t, J=8.8 Hz,2H), 2.69-2.54 (m, 4H), 2.41-2.35 (m, 2H), 2.24-2.18 (m, 2H).

2-((1-(4-fluorophenyl)-4-oxocyclohexyl)amino)pyrimidine-5-carbonitrile(FW)

To a stirred solution of compound FV (1.5 g, 7.23 mmol) in NMP (15 mL),2-chloropyrimidine-5-carbonitrile (AF, 1 g, 7.23 mmol) and DIPEA (6.3mL, 36.1 mmol) were added and the reaction mixture was heated to 130° C.for 5 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 50% EtOAc/hexane to afford compound FW (1 g, 44.6%)as an off white solid. LC-MS: m/z 311.05 [M+H]⁺.

2-((4,4-difluoro-1-(4-fluorophenyl)cyclohexyl)amino)pyrimidine-5-carbonitrile(FX)

To a stirred solution of compound FW (0.5 g, 1.61 mmol) in DCM (10 mL),BF₃.Et₂O (0.38 g, 2.73 mmol) and DAST (1.27 g, 7.88 mmol) were added andthe reaction mixture stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with saturated aqueous NaHCO₃ solution andextracted with DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 80%EtOAC/hexane to afford compound FX (0.35 g, 65.4%) as an off whitesolid. LC-MS: m/z 333.10 [M+H]⁺.

N-(4,4-difluoro-1-(4-fluorophenyl)cyclohexyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(FY)

To a stirred solution of compound FX (0.35 g, 1.05 mmol) in DMF (10 mL),NaN₃ (0.34 g, 5.26 mmol), NH₄Cl (0.28 g, 5.26 mmol) and LiCl (50 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was dissolved in cold water and adjust to pH=4-5 by usingHCl solution. The obtained solid was filtered, washed with water, driedto afford compound FY (0.18 g, crude) as an off white solid. LC-MS: m/z376.10 [M+H]⁺.

N-(4,4-difluoro-1-(4-fluorophenyl)cyclohexyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(37)

To a stirred solution of compound FY (0.18 g, 0.47 mmol) in DCM (5 mL),DFAA (0.5 mL) was added at 0° C. The reaction mixture was stirred at RTfor 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 10% MeOH/DCM to afford compound 37 (0.05 g, 24.6%)as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (br s, 1H), 8.69(br s, 1H), 7.50 (t, J=51.4 Hz, 1H), 7.46-7.42 (m, 2H), 7.10 (t, J=8.8Hz, 2H), 2.75-2.72 (m, 2H), 2.16-2.13 (m, 1H), 2.01-1.98 (m, 4H); LC-MS:m/z 426.1 [M+H]⁺; HPLC Purity: 99.7%.

Example 38N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide(38)

tert-butyl(2-(4-fluorophenyl)-2-oxoethyl)carbamate (GA)

To a stirred solution of 2-amino-1-(4-fluorophenyl)ethan-1-one (FZ, 5 g,26.7 mmol) in EtOH (250 mL), NaHCO₃(6.6 g, 79.1 mmol) and Boc anhydride(6.11 g, 28.0 mmol) were added and stirred at room temperature for 12 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was concentrated under reducedpressure. The residue was suspended in diethyl ether and the solidobtained was filtered, washed with pentane and dried to afford GA (6.1g, crude) as a white solid LC-MS: m/z 153.90 [M+H−100]⁺.

tert-butyl(2-amino-2-(4-fluorophenyl)ethyl)carbamate (GB)

To a stirred solution of compound GA (4 g, 15.7 mmol) in MeOH (125 mL),ammonium acetate (24.3 g, 315.8 mmol) was added and the reaction mixturewas stirred at RT for 30 min. NaCNBH₃ (2.67 g, 42.6 mmol) was added andthe reaction mixture was stirred at 60° C. for 3 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas diluted with EtOAC, basified with 10% NaOH solution and extractedwith EtOAC. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound GB (3.8 g, crude) as a brown oil. LC-MS: m/z 255.10 [M+H]⁺.

tert-butyl(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)carbamate(GC)

To a stirred solution of compound GB (3.5 g, 13.7 mmol) in ethanol (50mL), 2-chloropyrimidine-5-carbonitrile (AF, 2.11 g, 15.1 mmol) and DIPEA(7.17 mL, 41.1 mmol) were added and the reaction mixture was heated to90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 30% EtOAc/hexane to afford compound GC (4.6g, 93.8%) as a pale yellow solid. LC-MS: m/z 358.05 [M+H]⁺.

2-((2-amino-1-(4-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile (GD)

To a stirred solution of compound GC (4.6 g, 12.87 mmol) in DCM (100mL), TFA (10 mL) was added at 0° C. and stirred at room temperature for4 h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure to obtain compound GD as a TFA salt. The crude product wastriturated with diethyl ether and dried to afford compound GD (3 g,crude) as a white solid. LC-MS: m/z 258.0 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide(GE)

To a stirred solution of compound GD (1 g, 2.69 mmol) in DCM (20 mL),triethyl amine (1.12 mL 8.08 mmol) and mesyl chloride (0.31 mL, 4.04mmol) were added at 0° C. and the reaction mixture was stirred at RT for1 h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with saturated NaHCO₃solution and extracted with DCM. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was triturated with n-pentane and dried toafford compound GE (0.8 g, crude) as an off white solid. LC-MS: m/z336.0 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide(GF)

To a stirred solution of compound GD (0.8 g, 2.38 mmol) in DMF (10 mL),NaN₃ (0.77 g, 11.9 mmol), NH₄Cl (0.63 g, 11.9 mmol) and LiCl (250 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound GF(0.7 g, crude) as an off white solid. LC-MS: m/z 379.10 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide (38)

To a stirred solution of compound GF (0.33 g, 0.873 mmol) in DCM (10mL), DFAA (0.5 mL) was added at 0° C. Reaction mixture was stirred at RTfor 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 90% EtOAc/hexane to afford compound 38 (0.06 g,16%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=10.8Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 7.51 (t, J=51.2 Hz, 1H), 7.49-7.45 (m,3H), 7.25 (t, J=6.0 Hz, 1H), 7.17 (t, J=8.8 Hz, 2H), 5.30-5.24 (m, 1H),3.41-3.30 (m, 2H), 2.83 (s, 3H). LC-MS: m/z 429.05 [M+H]⁺; HPLC Purity:99.3%.

Chiral Preparative HPLC Details for 38(+) and 38(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (YMC CHIRALART CELLULOSE-SC®, 250×4.6mm, 5μ; Mobile Phase: A; 1% TFA in MTBE/B; IPA; Inj. Vol: 10.0 μL, Col.Temp.: 30° C.; Flow rate: 1.0 mL/min) to obtain 38(+) (65 mg) and 38(−)(60 mg).

38(+): ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.86 (s, 1H), 8.69 (d,J=8.4 HZ, 1H), 7.64-7.38 (m, 3H), 7.25 (t, J=5.4 Hz, 1H), 7.17 (t, J=8.8Hz, 2H), 5.30-5.24 (m, 1H), 3.43-3.38 (m, 1H), 2.83 (s, 3H). LC-MS: m/z429.30 [M+H]⁺; HPLC Purity: 99.3%.

38(−): ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.86 (s, 1H), 8.69 (d,J=8.8 HZ, 1H), 7.64-7.38 (m, 3H), 7.25 (t, J=5.6 Hz, 1H), 7.17 (t, J=8.8Hz, 2H), 5.30-5.24 (m, 1H), 3.43-3.34 (m, 1H), 2.83 (s, 3H). LC-MS: m/z429.10 [M+H]⁺; HPLC Purity: 99.1%.

Example 39N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide(39)

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide(GG)

To a stirred solution of compound GD (1 g, 2.69 mmol) in DCM (20 mL),triethyl amine (1.12 mL 8.08 mmol) and benzene sulphonyl chloride (0.71g, 4.04 mmol) were added at 0° C. and the reaction mixture was stirredat RT for 1 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withaqueous saturated NaHCO₃ solution and extracted with DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was trituratedwith n-pentane and dried to afford compound GG (0.7 g, crude) as a whitesolid. LC-MS: m/z 398.05 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide(GH)

To a stirred solution of compound GG (0.7 g, 1.76 mmol) in DMF (20 mL),NaN₃ (0.57 g, 8.80 mmol), NH₄Cl (0.47 g, 8.80 mmol) and LiCl (185 mg)were added and the reaction mixture was stirred at 95° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water, acidifiedwith 2N HCl solution to pH=2, and extracted with 10% MeOH/DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound GH(0.6 g, crude) as an off white solid. LC-MS: m/z 441.05 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide(39)

To a stirred solution of compound GH (0.3 g, 0.681 mmol) in DCM (10 mL),DFAA (0.5 mL) was added at 0° C. and the reaction mixture was stirred atRT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 70% EtOAc/hexane to afford compound 39 (0.11 g,32.9%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (br s,1H), 8.16 (br s, 1H), 8.63 (d, J=8.8 Hz, 1H), 7.92-7.90 (m, 1H),7.76-7.74 (m, 2H), 7.64-7.56 (m, 2H), 7.54 (t, J=51.2 Hz, 1H), 7.52-7.51(m, 1H), 7.40-7.36 (m, 2H), 7.13 (t, J=8.8 Hz, 2H), 5.23-5.17 (m, 1H),3.23-3.17 (m, 1H), 3.12-3.06 (m, 1H). LC-MS: m/z 491.05 [M+H]⁺; HPLCPurity: 98.9%.

Example 40N-(1-(2-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(40)

Example 40 was prepared in a manner analogous to the synthetic processused for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 7.54 (dd, J=7.6, 1.8 Hz, 1H),7.23-7.14 (m, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.88-6.79 (m, 1H), 3.84 (s,3H), 1.14-1.08 (m, 4H).

Example 41N-(1-(3-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(41)

Example 41 was prepared in a manner analogous to the synthetic processused for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05(s, 1H), 8.95-8.86 (m, 2H), 7.16 (t, J=7.8 Hz, 1H), 6.78-6.68 (m, 3H),3.69 (s, 3H), 1.38-1.23 (m, 4H).

Example 42N-(1-(4-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(42)

Example 42 was prepared in a manner analogous to the synthetic processused for the preparation of Example 1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06(s, 1H), 8.89 (d, J=2.3 Hz, 2H), 7.19-7.10 (m, 2H), 6.86-6.77 (m, 2H),3.69 (s, 3H), 1.29-1.17 (m, 4H).

Example 435-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3-methoxyphenyl)cyclopropyl)pyrimidin-2-amine(43)

Example 43 was prepared in a manner analogous to the synthetic processused for the preparation of Example 4. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99(s, 1H), 8.92-8.83 (m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.8 Hz,1H), 6.78-6.68 (m, 3H), 3.69 (s, 3H), 1.37-1.22 (m, 4H).

Example 445-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-methoxyphenyl)cyclopropyl)pyrimidin-2-amine(44)

Example 44 was prepared in a manner analogous to the synthetic processused for the preparation of Example 10. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99(s, 1H), 8.86 (d, J=3.5 Hz, 2H), 7.52 (t, J=52.2 Hz, 1H), 7.19-7.10 (m,2H), 6.85-6.75 (m, 2H), 3.69 (s, 3H), 1.28-1.11 (m, 4H).

Example 455-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl) pyrimidin-2-amine (45)

Example 45 was prepared in a manner analogous to the synthetic processused for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 9.09(s, 1H), 8.93 (d, J=2.9 Hz, 1H), 8.85 (d, J=3.0 Hz, 1H), 7.67-7.57 (m,2H), 7.52 (s, 1H), 7.37 (t, J=9.2 Hz, 2H), 1.49-1.33 (m, 4H).

Example 465-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-methoxyphenyl)cyclopropyl)pyrimidin-2-amine(46)

Example 46 was prepared in a manner analogous to the synthetic processused for the preparation of Example 10. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85(s, 1H), 8.78 (s, 1H), 8.57 (s, 1H), 7.62 (t, J=52.0 Hz, 1H), 7.57-7.47(m, 1H), 7.21-7.16 (m, 1H), 6.92 (dd, J=8.3, 1.1 Hz, 1H), 6.82-6.78 (m,1H), 3.83 (s, 3H), 1.16-1.12 (m, 4H).

Example 47N-(1-(4-bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(47)

Example 47 was prepared in a manner analogous to the synthetic processused for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03(s, 1H), 8.89 (brs, 1H), 8.85 (brs, 1H), 7.51 (t, J=52.0 Hz, 1H),7.44-7.42 (m, 2H), 7.12 (d, J=8.8 Hz, 2H), 1.35-1.27 (m, 4H).

Example 484-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl) benzonitrile (48)

Example 48 was prepared in a manner analogous to the synthetic processused for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08(s, 1H), 8.93 (d, J=3.0 Hz, 1H), 8.85 (d, J=3.1 Hz, 1H), 7.75-7.67 (m,2H), 7.52 (t, J=52.1 Hz, 1H), 7.35-7.27 (m, 2H), 1.51-1.44 (m, 2H),1.44-1.36 (m, 2H).

Example 495-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl) pyrimidin-2-amine (49)

Example 49 was prepared in a manner analogous to the synthetic processused for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10(s, 1H), 8.95-8.84 (m, 2H), 7.65 (t, J=52.1 Hz, 1H), 7.55-7.45 (m, 4H),1.48-1.39 (m, 2H), 1.35 (t, J=3.5 Hz, 2H).

Example 50N-(1-(4-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(50)

Example 50 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10(s, 1H), 8.95-8.84 (m, 2H), 7.65 (t, J=51.2 Hz, 1H), 7.55-7.45 (m, 4H),1.48-1.39 (m, 2H), 1.35 (t, J=3.5 Hz, 2H).

Example 51N-(1-(3-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(51)

Example 51 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05(s, 1H), 8.94-8.84 (m, 2H), 7.52 (t, J=51.1 Hz, 1H), 7.29 (t, J=7.8 Hz,1H), 7.20 (d, J=9.0 Hz, 2H), 7.13 (d, J=7.9 Hz, 1H), 1.41-1.28 (m, 4H).

Example 52N-(1-(2-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(52)

Example 52 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89(d, J=5.8 Hz, 2H), 8.82 (s, 1H), 7.83 (dd, J=7.0, 2.3 Hz, 1H), 7.51 (t,J=51.0 Hz, 1H), 7.41-7.34 (m, 1H), 7.26-7.22 (m, 2H), 1.30-1.16 (m, 4H).

Example 535-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (53)

Example 53 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06(s, 1H), 8.95-8.84 (m, 2H), 7.52 (t, J=51.2 Hz, 1H), 7.44-7.35 (m, 1H),7.22-7.07 (m, 3H), 1.42-1.31 (m, 4H).

Example 545-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (54)

Example 54 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06(s, 1H), 8.94-8.84 (m, 2H), 7.52 (t, J=51.2 Hz, 1H), 7.27 (t, J=8.3 Hz,4H), 1.41-1.27 (m, 4H).

Example 555-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-(trifluoromethoxy)phenyl)cyclopropyl) pyrimidin-2-amine (55)

Example 55 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91(s, 1H), 8.90-8.80 (m, 2H), 7.82 (dd, J=7.4, 1.9 Hz, 1H), 7.51 (t,J=51.4 Hz, 1H), 7.40-7.24 (m, 3H), 1.27-1.17 (m, 4H).

Example 565-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluorophenyl)cyclopropyl)pyrimidin-2-amine(56)

Example 56 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01(s, 1H), 8.85 (d, J=16.3 Hz, 2H), 7.67-7.57 (m, 1H), 7.37 (t, J=51.2 Hz,1H), 7.24-7.20 (m, 1H), 7.14-7.04 (m, 2H), 1.33-1.12 (m, 4H).

Example 575-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3-fluorophenyl)cyclopropyl)pyrimidin-2-amine(57)

Example 57 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03(s, 1H), 8.93-8.83 (m, 2H), 7.51 (t, J=51.2 Hz, 1H), 7.28-7.25 (m, 1H),7.03-6.88 (m, 3H), 1.42-1.26 (m, 4H).

Example 585-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl) pyrimidin-2-amine (58)

Example 58 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84(s, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.66-7.53(m, 1H), 7.50-7.43 (m, 1H), 7.42 (t, J=51.2 Hz, 1H), 7.40-7.38 (m, 1H),1.27 (s, 4H).

Example 595-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3,4-difluorophenyl)cyclopropyl)pyrimidin-2-amine (59)

Example 59 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02(s, 1H), 8.91-8.83 (m, 2H), 7.51 (t, J=51.4 Hz, 1H), 7.28-7.23 (m, 1H),7.22-7.11 (m, 1H), 7.06-6.98 (m, 1H), 1.39-1.23 (m, 4H).

Example 605-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,3-difluorophenyl)cyclopropyl)pyrimidin-2-amine (60)

Example 60 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10(s, 1H), 8.87 (d, J=9.8 Hz, 2H), 7.52 (t, J=51.4 Hz, 1H), 7.42 (dd,J=14.8, 7.5 Hz, 1H), 7.27 (q, J=8.4 Hz, 1H), 7.16-7.06 (m, 1H),1.39-1.19 (m, 4H).

Example 615-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,5-difluorophenyl)cyclopropyl)pyrimidin-2-amine (61)

Example 61 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06(s, 1H), 8.91 (s, 1H), 8.85 (s, 1H), 7.52 (t, J=51.4 Hz, 1H), 7.44-7.34(m, 1H), 7.22-7.04 (m, 2H), 1.38-1.28 (m, 2H), 1.28-1.16 (m, 2H).

Example 62N-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(62)

Example 62 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91(s, 1H), 8.85 (s, 1H), 8.79 (s, 1H), 7.85 (dd, J=8.7, 6.4 Hz, 1H), 7.49(t, J=51.4 Hz, 1H), 7.38-7.28 (m, 1H), 7.18-7.12 (m, 1H), 1.27-1.09 (m,4H).

Example 635-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluoro-2-(trifluoromethyl)phenyl)cyclopropyl) pyrimidin-2-amine (63)

Example 63 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85(d, J=19.1 Hz, 2H), 8.65 (s, 1H), 8.18 (dd, J=8.7, 5.9 Hz, 1H), 7.65 (t,J=51.2 Hz, 1H), 7.57-7.42 (m, 2H), 1.30 (s, 4H).

Example 64N-(1-(6-bromopyridin-3-yl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(64)

Example 64 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.07(s, 1H), 8.95-8.85 (m, 2H), 8.21 (d, J=1.7 Hz, 1H), 7.53 (t, J=51.2 Hz,1H), 7.40 (d, J=1.3 Hz, 2H), 1.41 (d, J=5.5 Hz, 2H), 1.32 (q, J=5.1 Hz,2H).

Example 655-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(pyridin-3-yl)cyclopropyl)pyrimidin-2-amine(65)

Example 65 was prepared in a manner analogous to the synthetic processused for the preparation of Example 18. ¹H NMR (400 MHz, DMSO-d₆) δ 9.09(s, 1H), 8.96-8.86 (m, 2H), 8.45-8.34 (m, 2H), 7.66 (t, J=51.4 Hz, 1H),7.61-7.51 (m, 1H), 7.31 (d, J=6.3 Hz, 1H), 1.46-1.38 (m, 2H), 1.37-1.29(m, 2H).

Example 66N-(1-(4-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(66)

Example 66 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05(s, 1H), 8.90-8.82 (m, 2H), 7.65 (t, J=8.5 Hz, 1H), 7.51 (t, J=51.4 Hz,1H), 7.41-7.28 (m, 1H), 7.24-7.16 (m, 1H), 1.33-1.16 (m, 4H).

Example 675-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)cyclopropyl)pyrimidin-2-amine (67)

Example 67 was prepared in a manner analogous to the synthetic processused for the preparation of Example 18. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08(s, 1H), 8.94 (d, J=3.1 Hz, 1H), 8.87 (d, J=3.1 Hz, 1H), 8.43 (d, J=2.9Hz, 1H), 7.66 (t, J=51.4 Hz, 1H), 7.61-7.50 (m, 1H), 7.29 (dd, J=8.9,4.3 Hz, 1H), 1.57 (q, J=4.3 Hz, 2H), 1.28 (q, J=4.3 Hz, 2H).

Example 685-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl) pyrimidin-2-amine (68)

Example 68 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01(s, 1H), 8.91-8.83 (m, 2H), 7.52 (t, J=51.4 Hz, 1H), 7.20-7.13 (m, 2H),6.94 (dd, J=8.8, 1.6 Hz, 2H), 4.74-4.62 (m, 2H), 1.25 (dd, J=12.2, 2.8Hz, 4H).

Example 69N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzyl) methanesulfonamide (69)

Example 69 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02(s, 1H), 8.92-8.81 (m, 2H), 7.65 (t, J=51.2 Hz, 1H), 7.54-7.42 (m, 1H),7.22 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 4.08 (d, J=6.1 Hz, 2H),2.84 (s, 3H), 1.28 (dd, J=13.2, 10.3 Hz, 4H).

Example 705-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl) cyclopropyl)pyrimidin-2-amine (70)

Example 70 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08(s, 1H), 8.87 (d, J=14.2 Hz, 2H), 7.77 (t, J=8.7 Hz, 1H), 7.52 (t,J=51.0 Hz, 1H), 7.29 (dd, J=11.0, 2.4 Hz, 1H), 7.19-7.12 (m, 1H),1.36-1.25 (m, 2H), 1.22 (t, J=3.4 Hz, 2H).

Example 715-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine (71)

Example 71 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13(s, 1H), 8.86 (d, J=2.9 Hz, 2H), 7.82 (t, J=7.9 Hz, 1H), 7.64 (t, J=51.1Hz, 1H), 7.62-7.47 (m, 2H), 1.44-1.32 (m, 2H), 1.32-1.22 (m, 2H).

Example 725-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3,5-difluorophenyl)cyclopropyl)pyrimidin-2-amine (72)

Example 72 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03(s, 1H), 8.96-8.85 (m, 2H), 7.52 (t, J=51.2 Hz, 1H), 7.02-6.98 (m, 1H),6.84-6.72 (m, 2H), 1.48-1.41 (m, 2H), 1.33 (q, J=5.6, 5.0 Hz, 2H).

Example 73N-(1-(3-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(73)

Example 73 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.09(s, 1H), 8.85 (d, J=11.2 Hz, 2H), 7.64-7.59 (m, 1H), 7.51 (t, J=51.2 Hz,1H), 7.44-7.38 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 1.33-1.30 (m, 2H),1.23-1.20 (m, 2H).

Example 745-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4,6-trifluorophenyl)cyclopropyl)pyrimidin-2-amine (74)

Example 74 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99(s, 1H), 8.83 (s, 2H), 7.51 (t, J=51.4 Hz, 1H), 7.07 (t, J=8.9 Hz, 2H),1.28-1.16 (m, 4H).

Example 755-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-5-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine (75)

Example 75 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10(s, 1H), 8.86 (d, J J=2.6 Hz, 2H), 7.67-7.56 (m, 1H), 7.52 (t, J=51.0Hz, 1H), 7.33-7.22 (m, 2H), 1.39-1.29 (m, 2H), 1.29-1.18 (m, 2H).

Example 76N-(1-(5-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(76)

Example 76 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ 9.07(s, 1H), 8.91 (s, 1H), 8.85 (s, 1H), 7.67-7.59 (m, 1H), 7.52 (t, J=51.2Hz, 1H), 7.35-7.31 (m, 1H), 7.18 (dd, J=10.4, 8.7 Hz, 1H), 1.38-1.26 (m,2H), 1.26-1.15 (m, 2H).

Example 77N-(1-(2-chloro-3-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(77)

Example 77 was prepared in a manner analogous to the synthetic processused for the preparation of Example 11. ¹H NMR (400 MHz, DMSO-d₆) δ8.90-8.78 (m, 3H), 7.71-7.61 (m, 1H), 7.51 (t, J=51.4 Hz, 1H), 7.25-7.11(m, 2H), 2.31 (s, 3H), 1.30-1.14 (m, 4H).

Examples 78(+) and 78(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide(78(+) and 78(−))

Example 78 was prepared in a manner analogous to the synthetic processes(and respective appropriate reagents and intermediates) used for thepreparation of other compounds exemplified herein.

Chiral Preparative SFC Details for 78(+) and 78(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-C02; B-0.1% NH₃ inMethanol; Gradient Elution 25-30% B, 1 min, 30-35% B, 2 min, 35% hold 8min, 35-50% in 4 min; Flow rate: 80.0 mL/min) to obtain 78(+) (60 mg)and 78(−) (60 mg).

78(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J=17.2 Hz, 2H), 8.68 (d,J=8.8 Hz, 1H), 8.03 (t, J=5.6 Hz, 1H), 7.64-7.39 (m, 3H), 7.15 (t, J=8.8Hz, 2H), 5.26-5.20 (m, 1H), 3.50-3.35 (m, 2H), 1.77 (s, 3H); LC-MS: m/z393.10 [M+H]⁺; HPLC: 99.08%; C-HPLC: 100.00% (RT: 4.03); SOR: +88.72,Solvent: Methanol, Path length: 10 mm, Concentration: 0.25 w/v %.

78(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J=17.2 Hz, 2H), 8.67 (d,J=8.4 Hz, 1H), 8.02 (t, J=5.6 Hz, 1H), 7.64-7.38 (m, 3H), 7.15 (t, J=8.8Hz, 2H), 5.25-5.20 (m, 1H), 3.50-3.35 (m, 2H), 1.76 (s, 3H); LC-MS: m/z393.15 [M+H]⁺; HPLC: 97.81%; C-HPLC: 99.40% (RT: 5.09); SOR: −62.00,Solvent: Methanol, Path length: 10 mm, Concentration: 0.5 w/v %.

Examples 103(+) and 103(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(103)

2-chloro-1-(2,4-difluorophenyl)ethan-1-one (GJ)

To a stirred solution of AlCl₃ (14.8 g, 131.4 mmol) in DCM (100 mL) wasadded 2-chloroacetyl chloride (23.3 g, 175.2 mmol) at 0° C. and stirredat RT for 1 h. To the resulting reaction mixture, a solution of1,3-difluorobenzene (GI, 10.0 g, 87.6 mmol) in DCM (20 mL) was addeddropwise at 0° C. and stirred at RT for 2 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with 1N HCl solution, neutralized with 2NNaOH solution and extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 10% EtOAc/hexane to afford compound GJ (14.1 g,84.5%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.08-8.02 (m,1H), 7.06-7.01 (m, 1H), 6.96-6.91 (m, 1H), 4.71 (s, 2H).

2-(2-(2,4-difluorophenyl)-2-oxoethyl)isoindoline-1,3-dione (GK)

To a stirred solution of phthalimide (12.0 g, 81.0 mmol) in DMF (30 mL)was added K₂CO₃ (20.3 g, 147.2 mmol) and the reaction mixture wasstirred at RT for 15 min. To the resulting reaction mixture, a solutionof compound GJ (14.0 g, 73.6 mmol) in DMF (20 mL) was added and thereaction mixture was stirred at RT for 16 h. The progress of reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was poured into crushed ice. The solid precipitate was filteredand then washed with water followed by hexane. The solid was dried underhigh vacuum to yield compound GK (9.5 g, 43.0%) as an off-white solid.¹H NMR (400 MHz, DMSO-d6): δ 8.07-8.01 (m, 1H), 7.97-7.89 (m, 4H),7.57-7.51 (m, 1H), 7.33-7.28 (m, 1H), 5.06 (s, 2H); LC-MS: m/z 302.0[M+H]⁺.

2-amino-1-(2,4-difluorophenyl)ethan-1-one hydrochloride (GL)

To a stirred solution of compound GK (9.5 g, 31.56 mmol) in EtOH (250mL) was added hydrazine hydrate (41.0 g, 63.12 mmol) and the reactionmixture was stirred at 90° C. for 1 h. The reaction mixture wasconcentrated under reduced pressure. To the crude residue was added 2NHCl and the resulting solution was heated to 50° C. for 15 min and thenstirred at RT for 30 min. The resulting precipitate was filtered and thefiltrate was concentrated under reduced pressure to yield crude compoundwhich was washed with diethyl ether and pentane and dried under vacuumto afford compound GL (6.1 g, 94.0%) as a brown solid. ¹H NMR (400 MHz,DMSO-d6): δ 11.18 (s, 1H), 8.51 (brs, 2H), 8.11-8.05 (m, 1H), 7.57-7.51(m, 1H), 7.35-7.29 (m, 1H), 4.39 (s, 2H); LC-MS: m/z 171.95 [M+H]⁺.

N-(2-(2,4-difluorophenyl)-2-oxoethyl)methanesulfonamide (GM)

To a stirred solution of compound GL (6.0 g, 29.13 mmol) in DCM (100 mL)was added triethylamine (12.7 mL, 87.38 mmol) and mesyl chloride (5.0 g,43.69 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for30 min. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NaHCO₃ solution. The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 18-20%EtOAc/hexane to afford compound GM (1.1 g, 15.0%) as an off-white solid.¹H NMR (400 MHz, CDCl₃): δ 8.12-8.06 (m, 1H), 7.08-7.01 (m, 1H),6.99-6.97 (m, 1H), 5.32 (brs, 1H), 4.60-4.58 (m, 2H), 3.03 (s, 3H).

N-(2-amino-2-(2,4-difluorophenyl)ethyl)methanesulfonamide (GN)

To a stirred solution of compound GM (1.1 g, 4.41 mmol) in MeOH (50 mL)was added ammonium acetate (6.81 g, 8.83 mmol) and the reaction mixturewas stirred at RT for 30 min. To the resulting reaction mixture, NaBH₃CN(0.75 g, 11.9 mmol) was added and the reaction mixture was stirred at80° C. for 16 h. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was dissolved withEtOAc and washed with a saturated NaHCO₃ solution. The organic layer wasseparated, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure to afford compound GN (1.0 g, 90.0%) as a light brown semisolid. LC-MS: m/z 251.0 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(GO)

To a stirred solution of compound GN (1.0 g, 4.00 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.56 g, 4.00 mmol) in EtOH (40mL) was added DIPEA (2.0 mL, 12.0 mmol) and the reaction mixture wasstirred at 90° C. for 16 h. The progress of reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude residue was dissolved inEtOAc and washed with water and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 7.5-8%EtOAc/hexane to afford compound GO (0.4 g, 29.0%) as an off-white solid.¹H NMR (400 MHz, CDCl₃): δ 8.52 (brs, 2H), 7.38-7.32 (m, 1H), 6.90-6.86(m, 2H), 6.68-6.66 (m, 1H), 5.51-5.46 (m, 1H), 4.59-4.56 (m, 1H), 3.62(t, J=6.4 Hz, 2H), 2.98 (s, 3H); LC-MS: m/z 354.05 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(GP)

To a stirred solution of compound GO (0.4 g, 1.13 mmol) in DMF (15 mL)was added NaN₃ (0.37 g, 5.66 mmol), NH₄Cl (0.31 g, 5.66 mmol) followedby LiCl (0.095 g) and the reaction mixture was stirred at 100° C. for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice water and acidified with 6NHCl solution to pH 4 and extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound GP (0.41 g,crude) as an off-white solid. LC-MS: m/z 397.05 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(103)

To a stirred solution of compound GP (0.4 g, 1.01 mmol) in DCM (15 mL)was added DFAA (0.17 mL, 1.5 mmol) at 0° C. and the reaction was stirredat RT for 16 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography using 8-10% EtOAc/hexane to afford racemic 103 (0.25 g,55.5%) as an off-white solid.

Chiral Preparative HPLC Details for 103(+) and 103(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A; n-Hexane+0.1% DEA/B; DCM:MeOH (1:1); Isocratic Elution 28% B;Flow rate: 30.0 mL/min) to obtain 103(+) (50 mg) and 103(−) (50 mg).

103(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=11.2 Hz, 2H), 8.70 (d,J=8.8 Hz, 1H), 7.65-7.39 (m, 2H), 7.34 (brs, 1H), 7.26-7.20 (m, 1H),7.12-7.08 (m, 1H), 5.56-5.50 (m, 1H), 3.37-3.30 (m, 2H), 2.86 (s, 3H);LC-MS: m/z 447.15 [M+H]⁺; C-HPLC: 98.13%; SOR: +21.04, Solvent:Methanol, Path length: 10 mm, Concentration: 0.5 w/v %.

103(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=11.6 Hz, 2H), 8.69 (brs,1H), 7.65-7.39 (m, 2H), 7.34 (brs, 1H), 7.26-7.20 (m, 1H), 7.12-7.07 (m,1H), 5.52 (brs, 1H), 3.40-3.30 (m, 2H), 2.86 (s, 3H); LC-MS: m/z 447.15[M+H]⁺; C-HPLC: 100%; SOR: −63.88, Solvent: Methanol, Path length: 10mm, Concentration: 0.5 w/v %.

Example 108N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)ethanesulfonamide(108)

Example 108 was prepared in a manner analogous to the synthetic processused for the preparation of Example 38. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(s, 1H), 8.86 (s, 1H), 8.67 (d, J=8.4 HZ, 1H), 7.64-7.38 (m, 3H), 7.28(s, 1H), 7.17 (t, J=8.8 Hz, 2H), 5.27-5.25 (m, 1H), 3.36 (br, 1H),2.95-2.92 (m, 2H), 1.08 (t, J=7.4 Hz, 3H).

Example 109N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-2-sulfonamide(109)

Example 109 was prepared in a manner analogous to the synthetic processused for the preparation of Example 38: ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(s, 1H), 8.86 (s, 1H), 8.66 (d, J=8.8 HZ, 1H), 7.64-7.38 (m, 3H),7.27-7.25 (m, 1H), 7.16 (t, J=8.6 Hz, 2H), 5.26-5.22 (m, 1H), 3.42-3.37(m, 1H), 3.12-3.09 (m, 1H), 1.14-1.12 (m, 6H).

Example 110N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanesulfonamide(110)

Example 110 was prepared in a manner analogous to the synthetic processused for the preparation of Example 38: ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(s, 1H), 8.86 (s, 1H), 8.68 (d, J=8.8 HZ, 1H), 7.64-7.30 (m, 4H), 7.17(t, J=8.8 Hz, 2H), 5.32-5.27 (m, 1H), 3.45-3.40 (m, 1H), 3.36 (t, J=6.6Hz, 1H), 0.89-0.87 (m, 4H).

Example 111N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-1-sulfonamide(111)

Example 111 was prepared in a manner analogous to the synthetic processused for the preparation of Example 38: ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(s, 1H), 8.86 (s, 1H), 8.68 (d, J=8.8 HZ, 1H), 7.64-7.39 (m, 3H), 7.28(br, 1H), 7.17 (t, J=8.6 Hz, 2H), 5.28-5.22 (m, 1H), 3.38-3.36 (m, 1H),2.93-2.782 (m, 2H), 1.59-1.52 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).

Example 112N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2-methylpropane-1-sulfonamide(112)

Example 112 was prepared in a manner analogous to the synthetic processused for the preparation of Example 38: ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(s, 1H), 8.86 (s, 1H), 8.67 (d, J=8.8 HZ, 1H), 7.64-7.38 (m, 3H), 7.27(t, J=5.8 Hz, 1H), 7.17 (t, J=9.0 Hz, 2H), 5.26-5.24 (m, 1H), 3.39-3.35(m, 1H), 2.80-2.78 (m, 2H), 2.01-1.98 (m, 1H), 0.94 (dd, J=6.6, 1.0 HZ,6H).

Example 113(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide(113(+))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide(113(+))

To a stirred solution of 38(+) (0.1 g, 0.23 mmol) in acetone (10 mL) wasadded dry K₂CO₃ (0.096 g, 0.70 mmol) and the reaction was stirred at RTfor 10 min. The reaction mixture was cooled to 0° C. and methyl iodide(0.132 g, 0.93 mmol) was added. The reaction mixture was allowed to stirat RT for 6 h and the reaction progress was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with acetone. The filtrate was evaporated underreduced pressure. The crude compound was purified by silica gel columnchromatography using 35% EtOAc/hexane to afford 113(+) (0.056 g, 54.0%)as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=6.8 Hz,2H), 8.73 (d, J=8.8 Hz, 1H), 7.65-7.39 (m, 3H), 7.19 (t, J=9.2 Hz, 2H),5.46-5.40 (m, 1H), 3.50-3.44 (m, 2H), 2.84 (s, 3H), 2.79 (s, 3H); LC-MS:m/z 443.15 [M+H]⁺; C-HPLC: 99.61% (RT: 7.22); SOR: +90.21, Solvent:Methanol, Path length: 10 mm, Concentration: 0.605 w/v %

Examples 115(+) and 115(−)N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(115)

1-(4-(difluoromethoxy)phenyl)ethan-1-one (3)

To a stirred solution of 4-hydroxyacetophenone (GQ, 5.0 g, 36.76 mmol)in DMF (50 mL) was added sodium 2-chloro-2,2-difluoroacetate (6.2 g,40.44 mmol) followed by NaOH (1.76 g, 44.11 mmol) and the reactionmixture was stirred at 100° C. for 14 h. After completion of thereaction, the reaction mixture was diluted with cold water and theproduct was extracted with EtOAc. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20-30%EtOAc/hexane to afford compound GR (3.5 g, 51.0%) as a colorless liquid.¹H NMR (400 MHz, DMSO-d6): δ 8.05-8.01 (m, 2H), 7.59-7.22 (m, 3H), 2.50(s, 3H); LC-MS: m/z 187.0 [M+H]⁺.

2-bromo-1-(4-(difluoromethoxy)phenyl)ethan-1-one (GS)

To a stirred solution of compound GR (3.5 g, 18.81 mmol) in ethylacetate (100 mL) was added copper(II) bromide (4.6 g, 20.69 mmol) andthe reaction mixture was stirred at RT for 24 h under N2 atmosphere. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was filtered through celite. The filtratewas concentrated under reduced pressure. The crude compound was purifiedby silica gel column chromatography using 10-20% DCM/hexane to affordcompound GS (3.0 g, 61.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d6):δ 8.08 (d, J=8.8 Hz, 2H), 7.62-7.25 (m, 3H), 4.92 (s, 2H).

2-amino-l-(4-(difluoromethoxy)phenyl)ethan-1-one (GT)

To a stirred solution of compound GS (4.0 g, 15.15 mmol) in EtOH (100mL) was added hexamethylenetetramine (3.2 g, 22.72 mmol) and thereaction mixture was stirred at RT for 2 h. The reaction mixture wascooled to 0° C., concentrated HCl (4 mL) was added and the reaction wasstirred at RT for 24 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure to afford compound GT (6g) as an off white solid which was used as such for the next step.LC-MS: m/z 201.95 [M+H]⁺.

N-(2-(4-(difluoromethoxy)phenyl)-2-oxoethyl)methanesulfonamide (GU)

To a stirred solution of compound GT (6.0 g, 29.85 mmol) in DCM (100 mL)was added triethylamine (8.4 mL, 59.70 mmol) and the reaction mixturewas stirred at RT for 30 min. To the reaction mixture, mesyl chloride(3.6 mL, 44.71 mmol) was added at 0° C. and the reaction mixture wasstirred at RT for 4 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith water and the product was extracted with DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 2% MeOH/DCM to afford compound GU (0.8 g, 9.5%) asan off white solid which was used for the next step without furtherpurification.

N-(2-amino-2-(4-(difluoromethoxy)phenyl)ethyl)methanesulfonamide (GV)

To a stirred solution of compound GU (0.8 g, 2.86 mmol) in MeOH (100 mL)was added ammonium acetate (4.4 g, 57.34 mmol) and the reaction mixturewas stirred at RT for 30 min. To the resulting reaction mixture, NaBH₃CN(0.49 g, 7.74 mmol) was added and the reaction mixture was stirred at80° C. for 12 h. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was diluted withwater and the product was extracted with 10% MeOH-DCM. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound GV (0.5 g, 62.5%) as a colorlesssemi solid which was used for the next reaction without furtherpurification.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)phenyl)ethyl)methanesulfonamide(GW)

To a stirred solution of compound GV (0.5 g, 1.78 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.37 g, 2.67 mmol) in EtOH (20mL) was added DIPEA (0.96 mL, 5.35 mmol) and the reaction mixture wasstirred at 90° C. for 14 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 2% MeOH/DCM to afford compound GW(0.35 g, 51.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.80(d, J=8.4 Hz, 1H), 8.69 (s, 2H), 7.46-7.39 (m, 2H), 7.38-7.14 (m, 4H),5.23-5.18 (m, 1H), 3.41-3.37 (m, 1H), 3.30-3.25 (m, 1H), 2.83 (s, 3H);LC-MS: m/z 384.05 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(GX)

To a stirred solution of compound GW (0.35 g, 0.91 mmol) in DMF (15 mL)was added NaN₃ (0.18 g, 2.74 mmol), NH₄Cl (0.15 g, 2.74 mmol) followedby LiCl (0.038 g, 0.91 mmol) and the reaction mixture was stirred at100° C. for 14 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The residue was quenched with ice water andacidified with 6N HCl solution to pH 4. The precipitate was filtered anddried under vacuum to afford compound GX (0.32 g, 82.0%) as a lightbrown sticky solid. H NMR (400 MHz, DMSO-d6): δ 8.85 (brs, 2H), 8.37 (d,J=8.4 Hz, 1H), 7.49-7.01 (m, 7H), 5.32-5.18 (m, 1H), 3.39-3.32 (m, 2H),2.83 (s, 3H); LC-MS: m/z 427.05 [M+H]⁺.

N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(115)

To a stirred solution of compound GX (0.32 g, 0.75 mmol) in DCM (30 mL)was added DFAA (0.17 mL, 1.5 mmol) at 0° C. and the reaction was stirredat RT for 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound which was purified by silica gelcolumn chromatography using 1-2% MeOH/DCM to afford racemic 115 (0.2 g,56.0%).

Chiral Preparative HPLC Details for 115(+) and 115(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A; n-Hexane+0.1% DEA/B; DCM:MeOH (1:1); Isocratic Elution 35% B;Flow rate: 30.0 mL/min) to obtain 115(+) (40 mg) and 115(−) (25 mg).

115(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=11.2 Hz, 2H), 8.70 (d,J=8.8 Hz, 1H), 7.64-7.39 (m, 3H), 7.38-7.01 (m, 4H), 5.30-5.24 (m, 1H),3.43-3.37 (m, 1H), 2.84 (s, 3H), one proton merged in solvent peak;LC-MS: m/z 477.20 [M+H]⁺. C-HPLC: 99.56% (RT: 9.47); SOR: +98.06,Solvent: Methanol, Path length: 10 mm, Concentration: 0.537 w/v %.

115(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J=12 Hz, 2H), 8.70 (d,J=9.2 Hz, 1H), 7.63-7.00 (m, 7H), 5.28-5.23 (m, 1H), 3.38-3.36 (m, 1H),2.83 (s, 3H), one proton merged in solvent peak; LC-MS: m/z 477.10[M+H]⁺. C-HPLC: 97.18% (RT: 10.90), SOR: −78.50, Solvent: Methanol, Pathlength: 10 mm, Concentration: 0.534 w/v %.

Examples 116(+) and 116(−)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(116(+) and 116(−))

1-(4-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (GZ)

To a stirred solution of 2′-fluoro-4′-hydroxyacetophenone (GY, 5.0 g,32.46 mmol) in DMF (50 mL) was added sodium 2-chloro-2,2-difluoroacetate(5.94 g, 38.96 mmol) followed by NaOH (1.55 g, 38.96 mmol) and thereaction mixture was stirred at 110° C. for 12 h. After completion ofthe reaction, the reaction mixture was diluted with cold water and theproduct was extracted with EtOAc. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20-30%EtOAc/hexane to afford compound GZ (3.0 g, 45.0%) as a colorless liquid.¹H NMR (400 MHz, DMSO-d6): δ 7.91 (t, J=8.6 Hz, 1H), 7.62-7.25 (m, 2H),7.14 (dd, J=2.4 Hz, 8.8 Hz, 1H), 2.56 (d, J=4.4 Hz, 3H); LC-MS: m/z204.85 [M+H]⁺.

2-bromo-1-(4-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (HA)

To a stirred solution of compound GZ (3.0 g, 14.70 mmol) in ethylacetate (60 mL) was added copper(II) bromide (3.93 g, 17.64 mmol) andthe reaction mixture was stirred at RT for 24 h under N2 atmosphere. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was filtered through celite. The filtratewas concentrated under reduced pressure. The crude compound was purifiedby silica gel column chromatography using 20-30% EtOAc/hexane to affordcompound HA (2.3 g, 55.0%) as a colorless liquid. ¹H NMR (400 MHz,DMSO-d6): δ 8.00 (t, J=8.8 Hz, 1H), 7.65-7.29 (m, 2H), 7.18 (dd, J=2.4Hz, 8.8 Hz, 1H), 4.82 (d, J=1.6 Hz, 2H).

2-amino-l-(4-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (HB)

To a stirred solution of compound HA (3.6 g, 12.7 mmol) in EtOH (50 mL)was added hexamethylenetetramine (2.7 g, 19.08 mmol) and the reactionmixture was stirred at RT for 2 h. To the resulting reaction mixture,concentrated HCl (3 mL) was added at 0° C. and stirred at RT for 24 h.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure to afford compound HB (4.0 g, crude) as anoff-white solid which was used as such for the next reaction. LC-MS: m/z220.05 [M+H]⁺.

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-oxoethyl)methanesulfonamide(HC)

To a stirred solution of compound HB (4.0 g, 14.13 mmol) in DCM (100 mL)was added triethylamine (5.9 mL, 42.40 mmol) and the reaction mixturewas stirred at RT for 30 min. To the resulting reaction mixture, mesylchloride (2.4 g, 21.20 mmol) was added at 0° C. and the reaction mixturewas stirred at RT for 4 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith water and the product was extracted with DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 30% EtOAc/hexane to afford compound HC (2.0 g,47.5%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.98 (d,J=8.6 Hz, 1H), 7.65-7.28 (m, 3H), 7.18 (d, J=8.8 Hz, 1H), 4.46 (brs,2H), 2.96 (s, 3H); LC-MS: m/z 297.90 [M+H]⁺.

N-(2-amino-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)methanesulfonamide(HD)

To a stirred solution of compound HC (1.0 g, 3.36 mmol) in MeOH (50 mL)was added ammonium acetate (5.2 g, 67.34 mmol) and the reaction mixturewas stirred at RT for 30 min. Then NaBH₃CN (0.58 g, 9.10 mmol) was addedand the reaction mixture was stirred at 80° C. for 12 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was diluted with water and the product wasextracted with 10% MeOH/DCM. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound HD (1.0 g, crude) as a colorless sticky solid. LC-MS: m/z299.00 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)methanesulfonamide(HE)

To a stirred solution of compound HD (1.0 g, 3.35 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.46 g, 3.35 mmol) in EtOH (25mL) was added DIPEA (1.8 mL, 10.06 mmol) and the reaction mixture wasstirred at 90° C. for 14 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure to yield crude product which waspurified by silica gel column chromatography using 40-50% EtOAc/hexaneto afford compound HE (0.55 g, 41.0%) as an off-white solid. ¹H NMR (400MHz, DMSO-d6): δ 8.79 (d, J=8.8 Hz, 1H), 8.71 (s, 2H), 7.56-6.81 (m,7H), 5.49-5.44 (m, 1H), 2.86 (s, 3H); LC-MS: m/z 402.10 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)methanesulfonamide(HF)

To a stirred solution of compound HE (0.55 g, 1.37 mmol) in DMF (20 mL)was added NaN₃ (0.27 g, 4.11 mmol) and NH₄Cl (0.22 g, 4.11 mmol)followed by LiCl (0.057 g, 1.37 mmol) and the reaction mixture wasstirred at 100° C. for 14 h. Progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was quenched with icewater and acidified with 6N HCl solution to pH 4. The precipitate wasfiltered and dried under vacuum to afford compound HF (0.6 g, crude) asa light brown semi solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.86-8.83 (m,2H), 8.40 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.60-7.51 (m, 1H), 7.46-7.03(m, 6H), 5.52-5.47 (m, 1H), 2.873 (s, 3H); LC-MS: m/z 445.15 [M+H]⁺.

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(116)

To a stirred solution of compound HF (0.6 g, 1.35 mmol) in DCM (20 mL)was added DFAA (0.29 mL, 2.70 mmol) at 0° C. and the reaction wasstirred at RT for 8 h. The progress of reaction was monitored by TLC.After completion of the reaction, the reaction mixture was quenched withwater and the product was extracted with DCM. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford racemic 116 (0.08 g,12.0%).

Chiral Preparative HPLC Details for 116(+) and 116(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A; n-Hexane+0.1% DEA/B; DCM:MeOH (6:4); Isocratic Elution 27% B;Flow rate: 30.0 mL/min) to obtain 116(+) (40 mg) and 116(−) (40 mg).

116(+): (0.04 g, 6.0%); ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=12.0 Hz,2H), 8.69 (d, J=8.4 Hz, 1H), 7.65-7.27 (m, 4H), 7.14-7.04 (m, 2H),5.56-5.50 (m, 1H), 3.38-3.35 (m, 2H), 2.87 (s, 3H); LC-MS: m/z 495.15[M+H]⁺. C-HPLC: 98.41% (RT: 13.70), SOR: +65.99, Solvent: Methanol, Pathlength: 10 mm, Concentration: 0.527 w/v %.

116(−): (0.04 g, 6.0%); ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=12.8 Hz,2H), 8.69 (d, J=8.4 Hz, 1H), 7.65-7.27 (m, 4H), 7.15-7.03 (m, 2H),5.56-5.50 (m, 1H), 3.40-3.36 (m, 2H), 2.87 (s, 3H); LC-MS: m/z 495.15[M+H]⁺. HPLC: 99.47% (RT: 11.37), SOR: −93.09, Solvent: Methanol, Pathlength: 10 mm, Concentration: 0.518 w/v %.

Example 118(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(118(+))

To a stirred solution of compound 38(+) (0.1 g, 0.23 mmol) in ACN (10mL), dry K₂CO₃ (0.1 g, 0.69 mmol) was added followed by2,2,2-trifluoroethyl trifluoromethanesulfonate (0.11 g, 0.47 mmol) andthe reaction mixture was stirred at 90° C. for 12 h. After 12 h,2,2,2-trifluoroethyl trifluoromethanesulfonate (0.11 g, 0.47 mmol) wasagain added and the reaction mixture was stirred at 90° C. for another12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in EtOAc and washed with water. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain crude compound as semi solid which was purified by silica gelcolumn chromatography using 35% EtOAc/hexane to afford compound 118(+)(0.06 g, 50.0%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.89(d, J=12 Hz, 2H), 8.68 (d, J=9.6 Hz, 1H), 7.64-7.39 (m, 3H), 7.20 (t,J=8.8 Hz, 2H), 5.56-5.54 (m, 1H), 4.22-4.09 (m, 2H), 3.71-3.61 (m, 2H),3.01 (s, 3H); LCMS: 511.15 (M+H); C-HPLC: 99.41% (RT: 19.55); SOR:+72.36, Solvent: Methanol, Path length: 10 mm, Concentration: 0.563 w/v%.

Examples 122(+) and 122(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(122(+) and 122(−))

2-bromo-1-(4-(trifluoromethoxy)phenyl)ethan-1-one (HH)

To a preheated (80° C.) stirred solution of copper(II) bromide (17.2 g,77.2 mmol) in EtOAc (20 mL) was added 4′-(trifluoromethoxy)acetophenone(HG, 8.7 g, 42.89 mmol) in chloroform (10 mL) and the reaction mixturewas stirred at 80° C. for 4 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas filtered through celite. The filtrate was concentrated under reducedpressure to yield crude compound which was purified by silica gel columnchromatography using 2-2.5% DCM/hexane to afford compound HH (7 g,58.0%) as an off white solid. ¹H NMR (400 MHz, CDCl3): δ 8.05 (d, J=8.0Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 4.41 (s, 2H).

2-amino-1-(4-(trifluoromethoxy)phenyl)ethan-1-one hydrochloride (HI)

To a stirred solution of compound HH (5.5 g, 19.5 mmol) in DCM (180 mL)was added hexamethylenetetramine (4.0 g, 29.2 mmol) and the reactionmixture was stirred at RT for 2 h. A white precipitate was obtainedwhich was filtered, washed with DCM and dried under high vacuum to getan off white solid. This solid was dissolved in EtOH (180 mL),concentrated HCl (10 mL) was added and the reaction mixture was stirredat RT for 12 h. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was washed withEtOAc and hexane and dried under high vacuum to afford compound HI (7.85g, crude) as an off white solid which was used as such for the nextreaction. 1H NMR (400 MHz, DMSO-d6): δ 8.49 (brs, 3H), 8.16 (d, J=8.8Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 4.62 (brs, 2H).

N-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide (HJ)

To a stirred solution of compound HI (2.7 g, 10.58 mmol) in DCM (100 mL)was added triethylamine (4.4 mL, 31.76 mmol) at 0° C. and the reactionmixture was stirred for 15 min. Then mesyl chloride (1.4 g, 12.70 mmol)was added dropwise and the reaction mixture was stirred at 0° C. for 30min. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with saturated NaHCO₃solution and the aqueous layer was extracted with DCM. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 20-22% EtOAc/hexane to afford compound HJ (0.66 g,21.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.12 (d,J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.45-7.43 (m, 1H), 4.65 (d, J=5.6Hz, 2H), 2.98 (s, 3H).

N-(2-amino-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide (HK)

To a stirred solution of compound HJ (0.2 g, 0.67 mmol) in MeOH (5 mL)was added ammonium acetate (1.03 g, 13.46 mmol) and the reaction mixturewas stirred at RT for 30 min. Then NaBH₃CN (0.12 g, 1.81 mmol) was addedand the reaction mixture was stirred at 80° C. for 4 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas diluted with water and basified with 10% NaOH solution to pH 10. Theaqueous layer was extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford compound HK (0.8 g, 67.0%) as a colorless sticky solid which wasused as such for the next reaction. ¹H NMR (400 MHz, DMSO-d6): δ 7.50(d, J=8.8 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.09 (brs, 1H), 3.40-3.95 (m,1H), 3.17 (s, 2H), 3.13-2.99 (m, 2H), 2.88-2.81 (m, 3H); LC-MS: m/z299.25 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(HL)

To a stirred solution of compound HK (0.2 g, 0.67 mmol) in EtOH (5 mL)was added DIPEA (0.25 g, 2.01 mmol) followed by2-chloropyrimidine-5-carbonitrile (AF, 0.09 g, 0.67 mmol) and thereaction mixture was stirred at 90° C. for 16 h. The progress ofreaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure to yield crudecompound which was purified by silica gel column chromatography using50% EtOAc/hexane to afford compound HL (0.7 g, 65.5%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.83 (d, J=8.4 Hz, 1H), 8.71 (d,J=2.8 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.27 (t,J=5.8 Hz, 1H), 5.27-5.21 (m, 1H), 3.46-3.34 (m, 2H), 2.84 (s, 3H);LC-MS: m/z 402.10 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(HM)

To a stirred solution of compound HL (0.7 g, 1.74 mmol) in DMF (10 mL)was added NaN₃ (0.34 g, 5.23 mmol) and NH₄Cl (0.28 g, 5.23 mmol)followed by LiCl (0.073 g, 1.74 mmol) and the reaction mixture wasstirred at 100° C. for 14 h. Progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was quenched with icewater and acidified with 6N HCl solution to pH 3. The aqueous phase wasextracted with ethyl acetate. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound HM (0.7 g, 90.5%) as an off white solid which was used as suchfor the next reaction. LC-MS: m/z 445.15 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(122)

To a stirred solution of compound HM (0.7 g, 1.57 mmol) in DCM (10 mL)was added DFAA (0.4 g, 2.36 mmol) at 0° C. and the reaction was stirredat RT for 5 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford crude compound which was purified by silicagel column chromatography using 20-30% EtOAc/hexane to afford racemic122 (0.4 g, 51.5%).

Chiral Preparative HPLC Details for 122(+) and 122(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A; n-Hexane+0.1% DEA/B; DCM:MeOH (6:4); Isocratic Elution 27% B;Flow rate: 30.0 mL/min) to obtain 122(+) (85 mg) and 122(−) (85 mg).

122(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=14.4 Hz, 2H), 8.74 (d,J=8.4 Hz, 1H), 7.65-7.35 (m, 5H), 7.29 (t, J=6.0 Hz, 1H), 5.33-5.28 (m,1H), 3.43-3.36 (m, 2H), 2.84 (s, 3H); LC-MS: m/z 495.15 [M+H]⁺. C-HPLC:96.03% (RT: 13.25), SOR: +70.02, Solvent: Methanol, Path length: 10 mm,Concentration: 0.539 w/v %

122(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=13.6 Hz, 2H), 8.74 (d,J=8.8 Hz, 1H), 7.65-7.35 (m, 5H), 7.29 (t, J=6.0 Hz, 1H), 5.34-5.28 (m,1H), 3.45-3.34 (m, 2H), 2.84 (s, 3H); LC-MS: m/z 495.15 [M+H]⁺. C-HPLC:99.65% (RT: 11.27), SOR: −105.59, Solvent: Methanol, Path length: 10 mm,Concentration: 0.543 w/v %.

Examples 123(+) and 123(−)N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(123(+) and 123(−))

tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (HO)

To a stirred solution of (tert-butoxycarbonyl)glycine (HN, 5.0 g, 28.57mmol) and triethylamine (4.1 mL, 31.42 mmol) in DCM (80 mL) was addedN,O-dimethylhydroxylamine (3.0 g, 31.42 mmol) followed by DCC (6.5 g,31.42 mmol) in DCM (20 mL) and the reaction mixture was stirred at RTfor 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with DCM. The filtrate was concentrated under reducedpressure to yield the crude compound which was purified by silica gelcolumn chromatography using 10% EtOAc/hexane to afford compound HO (6.0g, 97.0%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 5.27 (brs,1H), 4.08 (brs, 2H), 3.72 (s, 3H), 3.21 (s, 3H), 1.46 (s, 9H).

tert-butyl(2-cyclopropyl-2-oxoethyl)carbamate (HP)

To a stirred solution of compound HO (1.0 g, 4.59 mmol) in THF (20 mL)was added cyclopropylmagnesium bromide (0.5 M in THF) (45 mL, 22.93mmol) at 0° C. and the reaction mixture was stirred at RT for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with saturated NH₄Clsolution and the aqueous layer was extracted with EtOAc. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 40% EtOAc/hexane to afford compound HP (0.66 g,73.0%) as an off white solid. ¹H NMR (400 MHz, CDCl3): δ 5.25 (brs, 1H),4.17 (d, J=4.4 Hz, 2H), 1.92-1.86 (m, 1H), 1.42 (s, 9H), 1.09-1.06 (m,2H), 0.96-0.91 (m, 2H).

2-amino-1-cyclopropylethan-1-one hydrochloride (HQ)

To a stirred solution of compound HP (3.1 g, 15.57 mmol) in THF (15 mL)was added 1,4 dioxane.HCl (15.7 mL) at 0° C. and the reaction mixturewas stirred at RT for 4 h. The progress of reaction was monitored byTLC. The reaction mixture was concentrated under reduced pressure. Theobtained HCl salt was triturated with DCM and diethyl ether and driedunder vacuum to afford compound HQ (2.0 g, 95.0%) as an off white solid.¹H NMR (400 MHz, DMSO-d6): δ 8.17 (brs, 3H), 4.07 (s, 2H), 2.16-2.13 (m,1H), 1.06-0.99 (m, 2H), 0.98-0.94 (m, 2H).

N-(2-cyclopropyl-2-oxoethyl)methanesulfonamide (HR)

To a stirred solution of compound HQ (1.8 g, 13.33 mmol) in DCM (20 mL)was added triethylamine (5.3 mL, 39.99 mmol) at 0° C. and the reactionmixture was stirred for 30 min. To the resulting reaction mixture, mesylchloride (1.0 mL, 13.33 mmol) was added at 0° C. and the reactionmixture was stirred for 30 min. The progress of reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasquenched with water and the product was extracted with DCM. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The solid compound was triturated with diethyl etherto afford compound HR (2.2 g, 94.0%) as an off white solid. ¹H NMR (400MHz, CDCl₃): δ 5.12 (brs, 1H), 4.24 (d, J=5.2 Hz, 2H), 2.97 (s, 3H),1.96-1.90 (m, 1H), 1.19-1.15 (m, 2H), 1.08-1.03 (m, 2H).

N-(2-amino-2-cyclopropylethyl)methanesulfonamide (HS)

To a stirred solution of compound HR (2.7 g, 15.25 mmol) in MeOH (27 mL)was added ammonium acetate (23.5 g, 305.08 mmol) and the reactionmixture was stirred at RT for 30 min. Then NaBH₃CN (2.3 g, 38.0 mmol)was added portion wise at 0° C. and the reaction mixture was stirred at65° C. for 12 h. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was quenched withwater and basified with 10% NaOH solution to pH 9-10. The aqueous phasewas extracted with DCM. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound HS (1.5 g, 55.0%) as a light brown semi solid which was used assuch for the next step. ¹H NMR (400 MHz, DMSO-d6): δ 3.05-3.03 (m, 1H),2.90 (s, 3H), 2.88-2.82 (m, 1H), 2.17-2.12 (m, 1H), 0.74-0.66 (m, 1H),0.40-0.30 (m, 2H), 0.25-0.16 (m, 2H).

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-cyclopropylethyl)methanesulfonamide(HT)

To a stirred solution of compound HS (1.5 g, 8.43 mmol) in EtOH (20 mL)was added DIPEA (4.3 g, 25.28 mmol) followed by2-chloropyrimidine-5-carbonitrile (AF, 1.2 g, 8.43 mmol) and thereaction mixture was stirred at 90° C. for 6 h. The progress of reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 50% EtOAc/hexane. Theproduct was further triturated with diethyl ether and pentane to affordcompound HT (1.01 g, 42.0%) as an off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.67-8.65 (m, 2H), 8.21 (d, J=8.8 Hz, 1H), 7.07 (t, J=6.2Hz, 1H), 3.64-3.56 (m, 1H), 3.32-3.13 (m, 2H), 2.87 (s, 3H), 1.06-0.85(m, 1H), 0.52-0.46 (m, 1H), 0.40-0.34 (m, 1H), 0.32-0.19 (m, 2H); LC-MS:m/z 282.05 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-cyclopropylethyl)methanesulfonamide(HU)

To a stirred solution of compound HT (1.0 g, 3.59 mmol) in DMF (10 mL)was added NaN₃ (1.15 g, 17.79 mmol), NH₄Cl (0.96 g, 17.79 mmol) followedby LiCl (0.3 g) and the reaction mixture was stirred at 100° C. for 6 h.Progress of the reaction was monitored by TLC. After completion of thereaction, DMF was removed under reduced pressure. The residue wasquenched with ice water and acidified with 6N HCl solution to pH 4. Theaqueous layer was extracted with 10% MeOH/DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford compound HU (1.12 g, 97.0%) as a light brown solidwhich was used as such for the next step. ¹H NMR (400 MHz, DMSO-d6): δ8.83 (s, 2H), 7.80 (d, J=8.8 Hz, 1H), 7.07 (t, J=6.2 Hz, 1H), 3.68-3.63(m, 1H), 3.23-3.16 (m, 3H), 2.89 (s, 3H), 1.06-1.02 (m, 1H), 0.50-0.46(m, 1H), 0.41-0.32 (m, 2H), 0.27-0.23 (m, 1H); LC-MS: m/z 325.05 [M+H]⁺.

N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(123)

To a stirred solution of compound HU (1.1 g, 3.39 mmol) in DCM (40 mL)was added DFAA (0.6 mL, 6.70 mmol) at 0° C. and the reaction was stirredat RT for 12 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand basified to pH 7-8 using aq. NaHCO₃. The aqueous phase was extractedwith DCM. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography using 25% EtOAc/hexane. The compoundwas further triturated with diethyl ether and pentane to afford racemic123 (0.5 g, 41.0%) as an off white solid.

Chiral Preparative SFC Details for 123(+) and 123(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IA, 250×30 mm, 5μ; Mobile Phase: A; CO₂/B; 0.1% NH₃ inMethanol; Gradient Elution 20% B, 5 min, 20-25% in 4 min, 25-30% in 3min, 30% B hold 13 min; Flow rate: 80.0 mL/min) to obtain 123(+) (61 mg)and 123(−) (44 mg).

123(+): (0.061 g, 4.8%); ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 2H), 8.12(d, J=8.8 Hz, 1H), 7.65-7.39 (m, 1H), 7.09 (t, J=6.2 Hz, 1H), 3.69-3.66(m, 1H), 3.27-3.18 (m, 2H), 2.88 (s, 3H), 1.05-1.02 (m, 1H), 0.51-0.47(m, 1H), 0.40-0.32 (m, 2H), 0.26-0.23 (m, 1H); LC-MS: m/z 375.10 [M+H]⁺;C-HPLC: 100% (RT: 3.94); SOR: +31.56, Solvent: Methanol, Path length: 10mm, Concentration: 0.64 w/v %.

123(−): (0.044 g, 3.5%); ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 2H), 8.12(d, J=8.8 Hz, 1H), 7.65-7.39 (m, 1H), 7.09 (t, J=6.2 Hz, 1H), 3.69-3.66(m, 1H), 3.25-3.18 (m, 2H), 2.88 (s, 3H), 1.07-1.02 (m, 1H), 0.51-0.48(m, 1H), 0.40-0.32 (m, 2H), 0.28-0.23 (m, 1H); LC-MS: m/z 375.10 [M+H]⁺;C-HPLC: 100% (RT: 4.82); SOR: −14.83, Solvent: Methanol, Path length: 10mm, Concentration: 0.53 w/v %.

Example 125N-(3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide(125)

3-bromo-1-(4-fluorophenyl)propan-1-one (HV)

To a stirred solution of AlCl₃ (6.9 g, 52 mmol) in DCM (50 mL) was added3-bromopropanoyl chloride (5.2 mL, 52 mmol) at 0° C. and the reactionmixture was stirred at RT for 1 h. Fluorobenzene (CV, 5.0 g, 52 mmol)dissolved in DCM (10 mL) was added dropwise at 0° C. and the reactionmixture was stirred at RT for 2 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with water, neutralized with 2N NaOH solution and extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound HV (11.0 g, 92.0%) as a black solid. ¹H NMR (400 MHz, CDCl3): δ8.03-7.98 (m, 2H), 7.17 (t, J=8.6 Hz, 2H), 3.75 (t, J=7.0 Hz, 2H), 3.56(t, J=6.8 Hz, 2H).

3-azido-l-(4-fluorophenyl)propan-1-one (HW)

To a stirred solution of compound HV (5.0 g, 21.7 mmol) in MeOH (200 mL)was added NaN₃ (4.2 g, 65.1 mmol) followed by KI (35 mg) in water (30mL) and the reaction mixture was stirred at 60° C. for 2.5 h. Theprogress of reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The crude residue was dissolved in EtOAc and washed with water. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound HW (3.5 g, 86.0%) as a brown stickysemi solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.09-8.06 (m, 2H), 7.37 (t,J=8.6 Hz, 2H), 3.65 (t, J=6.2 Hz, 2H), 3.36 (t, J=6.2 Hz, 2H).

3-amino-1-(4-fluorophenyl)propan -1l-one hydrochloride (HX)

To a stirred solution of compound HW (3.5 g, 18.13 mmol) in MeOH (100mL) and cone. HCl (12 mL) was added Pd/C (0.35 g, 10% w/w) under N2atmosphere. The reaction mixture was stirred under H₂ balloon pressureat RT for 2 h. After completion of the reaction, the reaction mixturewas filtered through celite and washed thoroughly with MeOH. Thefiltrate was concentrated under reduced pressure to afford compound HX(2.4 g, 92.0%) as a brown sticky semi solid. LC-MS: m/z 168.00 [M+H]⁺.

N-(3-(4-fluorophenyl)-3-oxopropyl)methanesulfonamide (HY)

To a stirred solution of compound HX (2.4 g, 11.8 mmol) in DCM (100 mL)was added triethyl amine (4.9 mL, 35.4 mmol) at 0° C. and the reactionmixture was stirred for 15 min. Then mesyl chloride (2.0 g, 17.82 mmol)dissolved in DCM (25 mL) was added dropwise at 0° C. and the reactionmixture was stirred for 45 min. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with saturated NaHCO₃ solution. The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 2-5% MeOH/DCM to afford compound HY (2.1 g, 73.0%)as an off white solid. LC-MS: m/z 246.00 [M+H]⁺.

N-(3-amino-3-(4-fluorophenyl)propyl)methanesulfonamide (HZ)

To a stirred solution of compound HY (2.1 g, 8.5 mmol) in MeOH (20 mL)was added ammonium acetate (13.0 g, 171.4 mmol) and the reaction mixturewas stirred at RT for 30 min. To the resulting reaction mixture, NaBH₃CN(1.4 g, 23.1 mmol) was added and the reaction mixture was stirred at 75°C. for 16 h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was diluted with EtOAcand washed with saturated NaHCO₃ solution. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound HZ (1.75 g, 83.0%) as a brown sticky semi solid. ¹H NMR (400MHz, DMSO-d6): δ 7.43-7.39 (m, 2H), 7.16 (t, J=8.8 Hz, 2H), 4.05-3.95(m, 2H), 2.92-2.89 (m, 1H), 2.88-2.79 (m, 4H), 1.99 (s, 1H), 1.83-1.73(m, 2H), 1.18 (t, J=7.0 Hz, 1H); LC-MS: m/z 247.05 [M+H]⁺.

N-(3-((5-cyanopyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide(IA)

To a stirred solution of compound HZ (0.6 g, 2.4 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.34 g, 2.4 mmol) in EtOH (15 mL)was added DIPEA (1.2 mL, 7.2 mmol) and the reaction mixture was stirredat 90° C. for 16 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude residue was dissolved in EtOAc and washedwith water and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 50% EtOAc/hexane to affordcompound IA (0.4 g, 47.5%) as an off white solid. ¹H NMR (400 MHz,CDCl3): δ 8.51 (d, J=22.4 Hz, 2H), 7.35-7.32 (m, 2H), 7.08 (t, J=8.4 Hz,2H), 5.98 (d, J=8.8 Hz, 1H), 5.27-5.22 (m, 1H), 4.93-4.90 (m, 1H),3.30-3.23 (m, 1H), 3.19-3.12 (m, 1H), 2.95 (s, 3H), 2.21-2.16 (m, 2H);LC-MS: m/z 350.20 [M+H]⁺.

N-(3-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide(IB)

To a stirred solution of compound IA (0.4 g, 1.14 mmol) in DMF (15 mL)was added NaN₃ (0.31 g, 5.7 mmol) and NH₄Cl (0.37 g, 5.7 mmol) followedby LiCl (0.09 g) and the reaction mixture was stirred at 100° C. for 16h. Progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice water and acidified with 6NHCl solution to pH 4. The product was extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound IB (0.33 g,73.5%) as a sticky mass. LC-MS: m/z 393.45 [M+H]⁺.

N-(3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide(125)

To a stirred solution of compound IB (0.32 g, 0.83 mmol) in DCM (15 mL)was added DFAA (0.22 mL, 1.24 mmol) at 0° C. and the reaction wasstirred at RT for 16 h. The progress of reaction was monitored by TLC.After completion of the reaction, the reaction mixture was quenched withwater and the product was extracted with DCM. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford crude compound which was purified bysilica gel column chromatography using 5% MeOH/DCM to afford 125 (0.065g, 17.5%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ 8.86-8.83 (m, 3H), 7.64-7.38 (m, 3H), 7.15(t, J=9.2 Hz, 2H), 7.07 (t, J=5.6 Hz, 1H), 5.23-5.17 (m, 1H), 3.08-2.93(m, 2H), 2.85 (s, 3H), 2.11-2.02 (m, 1H), 1.99-1.87 (m, 1H); LC-MS: m/z443.15 [M+H]⁺, HPLC: 95.64%.

Example 127N-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)methanesulfonamide(127)

tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (ID)

To a stirred solution of (tert-butoxycarbonyl)alanine (IC, 10.0 g, 52.8mmol) in DMF (100 mL) was added EDCI.HCl (15.1 g, 79.2 mmol) and HOBT(10.8 g, 79.2 mmol) followed by triethylamine (15 mL, 105.7 mmol) andthe reaction mixture was stirred at RT for 30 min. To the resultingreaction mixture, N,O-dimethylhydroxylamine hydrochloride (15.4 g, 158.5mmol) was added at 0° C. and the reaction mixture was stirred at RT for12 h. The progress of reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was quenched with ice cold water andthe product was extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound ID (5.0 g, 41.0%) as an off white solid.¹H NMR (400 MHz, DMSO-d6): δ 7.04 (d, J=7.6 Hz, 1H), 4.41-4.37 (m, 1H),3.72 (s, 3H), 3.09 (s, 3H), 1.36 (s, 9H), 1.14 (d, J=7.2 Hz, 3H).

tert-butyl(1-(4-fluorophenyl)-1-oxopropan-2-yl)carbamate (IF)

To magnesium turnings (3.3 g, 137.93 mmol) in dry THF (40 mL) under N2atmosphere, 1-bromo-4-fluorobenzene (24.1 g, 137.93 mmol) was added andthe mixture was stirred at RT for 30 min. Compound ID (4.0 g, 17.24mmol) in THF (20 mL) was added and the reaction mixture was stirred atRT for 12 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NH₄Cl solution and the product was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 40% EtOAc/hexane to afford compound IE (3.0g, 65%) as an off white solid. LC-MS: m/z 168 [M-Boc+H]⁺.

2-amino-1-(4-fluorophenyl)propan-1-one hydrochloride (IF)

To a stirred solution of compound IE (3.0 g, 11.23 mmol) in EtOAc (30mL) was added HCl in EtOAc (15 mL) at 0° C. and the reaction mixture wasstirred at RT for 12 h. The reaction mixture was diluted with EtOAc andthe solid was filtered off and dried under vacuum to afford compound IF(2.1 g, 92%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.55 (brs,3H), 8.18-8.15 (m, 2H), 7.43 (t, J=8.8 Hz, 2H), 5.12 (q, J=7.0 Hz, 1H),1.42 (d, J=7.6 Hz, 3H); LC-MS: m/z 168 [M+H]⁺.

N-(1-(4-fluorophenyl)-1-oxopropan-2-yl)methanesulfonamide (IG)

To a stirred solution of compound IF (2.0 g, 9.85 mmol) and mesylchloride (1.13 mL, 14.77 mmol) in DCM (30 mL) was added triethyl amine(4.15 mL, 29.55 mmol) at 0° C. and the reaction mixture was stirred atRT for 8 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound IG (1.5 g, 62.0%) as a white solid. ¹HNMR (400 MHz, DMSO-d6): δ 8.14-8.10 (m, 2H), 7.39 (t, J=8.8 Hz, 2H),5.13-5.09 (m, 1H), 2.94 (s, 3H), 1.30 (d, J=6.8 Hz, 3H); LC-MS: m/z246.2 [M+H]⁺.

N-(1-amino-l-(4-fluorophenyl)propan-2-yl)methanesulfonamide (IH)

To a stirred solution of compound IG (1.5 g, 6.12 mmol) in MeOH (20 mL)was added ammonium acetate (9.4 g, 122.24 mmol) and the reaction mixturewas stirred at RT for 30 min. Then NaBH₃CN (1.0 g, 16.53 mmol) was addedportion wise at 0° C. and the reaction mixture was stirred at 80° C. for12 h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was quenched with waterand basified with 10% NaOH solution to pH 9-10. The aqueous phase wasextracted with DCM. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound IH(1.5 g, crude) as a sticky solid which was used as such for the nextreaction. LC-MS: m/z 246.95 [M+H]⁺.

N-(1-((5-cyanopyrimidin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)methanesulfonamide(II)

To a stirred solution of compound IH (1.5 g, 6.09 mmol) in EtOH (30 mL)was added DIPEA (3.3 mL, 18.29 mmol) followed by2-chloropyrimidine-5-carbonitrile (AF, 0.94 g, 6.70 mmol) and thereaction mixture was stirred at 90° C. for 12 h. The progress ofreaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 2-5%MeOH/DCM to afford compound II (1.2 g, 57.0%) as an off white solid.LC-MS: m/z 350.05 [M+H]⁺.

N-(1-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)methanesulfonamide(IJ)

To a stirred solution of compound II (0.5 g, 1.43 mmol) in DMF (15 mL)was added NaN₃ (0.28 g, 4.29 mmol) and NH₄Cl (0.23 g, 4.29 mmol)followed by LiCl (0.06 g, 1.43 mmol) and the reaction mixture wasstirred at 100° C. for 14 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, it was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 1N HCl solution. The aqueous layer was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford compound JJ (0.35 g, 62.5%) as a whitesolid which was used as such for the next reaction. LC-MS: m/z 393.45[M+H]⁺.

N-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)methanesulfonamide(127)

To a stirred solution of compound IJ (0.35 g, 0.89 mmol) in DCM (10 mL)was added DFAA (0.19 mL, 1.78 mmol) at 0° C. and the reaction wasstirred at RT for 4 h. The progress of reaction was monitored by TLC.After completion of the reaction, the reaction mixture was diluted withDCM, washed with saturated NaHCO₃ solution. Organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography using 2-5%MeOH/DCM to afford a mixture of diastereomers 127A (0.06 g, 15.0%) and127B (0.01 g, 2.5%) as an off-white solid.

127A: ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J=10.8 Hz, 2H), 8.68 (d,J=9.2 Hz, 1H), 7.64-7.38 (m, 3H), 7.24 (d, J=8.8 Hz, 1H), 7.16 (t, J=8.8Hz, 2H), 5.08 (t, J=8.8 Hz, 1H), 3.77-3.69 (m, 1H), 2.38 (s, 3H), 1.22(d, J=6.8 Hz, 3H); LC-MS: m/z 443.10 [M+H]⁺; HPLC: 94.78%.

127B: ¹H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=21.6 Hz, 2H), 8.49 (d,J=9.2 Hz, 1H), 7.64-7.39 (m, 3H), 7.18 (t, J=7.7 Hz, 3H), 5.21 (t, J=7.6Hz, 1H), 3.79-3.74 (m, 1H), 2.58 (s, 3H), 1.11 (d, J=6.4 Hz, 3H); LC-MS:m/z 443.10 [M+H]⁺; HPLC: 73.71%.

Example 128N-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(128)

(4-fluorophenyl)(3-nitrophenyl)methanone (IL)

To a stirred solution of 3-nitrobenzoic acid (IK, 5.0 g, 29.94 mmol) inDCE (50 mL), thionyl chloride (2.5 mL, 38.92 mmol) was added at 0° C.and the reaction was stirred at 50° C. for 2 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction was cooled to 0° C., fluorobenzene (CV, 13.9 mL, 149.2 mmol)and AlCl₃ (4.36 g, 32.82 mmol) were added and the reaction was stirredat RT for 6 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with 1NHCl solution and the product was extracted with DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was trituratedwith diethyl ether to afford IL (6.0 g, 82.0%) as a pale yellow solid.¹H NMR (400 MHz, DMSO-d6): δ 8.52-8.49 (m, 1H), 8.43 (s, 1H), 8.15 (d,J=8.0 Hz, 1H), 7.91-7.84 (m, 3H), 7.46-7.41 (m, 2H).

(3-aminophenyl)(4-fluorophenyl)methanone (IM)

To a stirred solution of compound IL (2.0 g, 8.16 mmol) in IPA (20 mL),iron powder (2.28 g, 40.81 mmol) and NH₄Cl (2.20 g, 40.81 mmol) in (20mL) water were added and the reaction was stirred at 80° C. for 3 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was filtered, washed with MeOH and thefiltrate was concentrated under reduced pressure. The residue wasquenched with water and the product was extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product wastriturated with diethyl ether to afford IM (1.7 g, 96.0%) as a lightyellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.80-7.77 (m, 2H), 7.39-7.35(m, 2H), 7.19-7.15 (m, 1H), 6.92 (s, 1H), 6.84-6.79 (m, 2H), 5.40 (s,2H).

N-(3-(4-fluorobenzoyl)phenyl)methanesulfonamide (IN)

To a stirred solution of compound IM (1.7 g, 7.90 mmol) in DCE (20 mL),pyridine (1.3 mL, 15.8 mmol) and mesyl chloride (0.9 mL, 11.86 mmol)were added at 0° C. and stirred for 2 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was quenched with water and the product was extracted with DCM.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 30% EtOAc/hexane toafford IN (1.5 g, 65.0%) as an off-white semisolid. LC-MS: m/z 294.25[M+H]⁺.

N-(3-(amino(4-fluorophenyl)methyl)phenyl)methanesulfonamide (IO)

To a stirred solution of compound IN (1.5 g, 5.11 mmol) in MeOH (20 mL),ammonium acetate (7.8 g, 102.3 mmol) and NaBH₃CN (0.98 g, 15.35 mmol)were added and the reaction was stirred at 80° C. for 2 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was diluted with water and the product wasextracted with DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford IO (0.95 g, 63%) as a light brown semisolid. ¹H NMR (400 MHz,DMSO-d6): δ 7.42-7.38 (m, 2H), 7.25-7.21 (m, 2H), 7.14-7.08 (m, 3H),7.04-7.01 (m, 1H), 5.09-5.08 (m, 1H), 2.95 (s, 3H).

N-(3-(((5-cyanopyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(IP)

To a stirred solution of compound IO (0.91 g, 3.29 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.55 g, 3.95 mmol) in EtOH (10mL), DIPEA (1.6 mL, 9.87 mmol) was added and the reaction was stirred at90° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 15% EtOAc/hexane to afford compound IP (0.7g, 53.0%) as an off white semisolid. LC-MS: m/z 397.80 [M+H]⁺.

N-(3-(((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(IQ)

To a stirred solution of compound IP (600 mg, 1.51 mmol) in DMF (10 mL),NaN₃ (491 mg, 7.55 mmol), NH₄Cl (408 mg, 7.55 mmol) and LiCl (180 mg)were added and the reaction was stirred at 100° C. for 12 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 2N HCl solution to pH=4. The product was extracted with 10% MeOH inDCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford IQ(500 mg, 75.0%) as an off white solid. LC-MS: m/z 441.10 [M+H]⁺.

N-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(128)

To a stirred solution of compound IQ (500 mg, 1.13 mmol) in DCM (10 mL),DFAA (1 mL) was added at 0° C. and the reaction was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with 10% NaHCO₃solution and the product was extracted with DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 35% EtOAc/hexane to affordcompound 128 (60 mg, 10.0%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 9.72 (s, 1H), 9.23 (d, J=8.8 Hz, 1H), 8.90 (d, J=6.8 Hz,2H), 7.64-7.38 (m, 3H), 7.29-7.25 (m, 1H), 7.18-7.14 (m, 3H), 7.08-7.05(m, 2H), 6.44 (d, J=8.8 Hz, 1H), 2.95 (s, 3H); LC-MS: 491.15 [M+H]⁺,HPLC: 97.13%.

Example 129N-(4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(129)

(4-fluorophenyl)(4-nitrophenyl)methanone (IS)

To a stirred solution of AlCl₃ (13.9 g, 104.1 mmol) in DCM (150 mL),4-nitrobenzoyl chloride (IR, 14.5 g, 78.1 mmol) was added at 0° C. andstirred at RT for 1 h. To the resulting reaction mixture, fluorobenzene(CV, 5.0 g, 52.0 mmol) was added and the reaction was stirred at RT for2 h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with 1N HCl solution,neutralized with 2N NaOH solution and the product was extracted withEtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 10%EtOAc/hexane to afford IS (5.0 g, 40.0%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.38 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H),7.89-7.86 (m, 2H), 7.46-7.41 (m, 2H).

(4-aminophenyl)(4-fluorophenyl)methanone (IT)

To a stirred solution of compound IS (5.0 g, 20.0 mmol) in IPA (30 mL),iron powder (5.7 g, 102.0 mmol) and NH₄Cl (5.5 g, 102.0 mmol) in water(30 mL) were added and the reaction was stirred at 80° C. for 3 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was diluted with waterand the product was extracted with EtOAc. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 10% EtOAc/hexane to afford IT (4.0 g, 92.0%) as alight yellow semisolid. ¹H NMR (400 MHz, DMSO-d6): δ 7.69-7.65 (m, 2H),7.51 (d, J=8.8 Hz, 2H), 7.34-7.30 (m, 2H), 6.60 (d, J=8.8 Hz, 2H), 6.17(s, 2H).

N-(4-(4-fluorobenzoyl)phenyl)methanesulfonamide (IU)

To a stirred solution of compound IT (4.6 g, 21.39 mmol) in pyridine (60mL), mesyl chloride (1.7 mL, 32.0 mmol) was added at 0° C. and stirredat RT for 4 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with EtOAc. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 10% EtOAc/hexane to afford IU (4.4 g, 71.0%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 7.81-7.73(m, 4H), 7.40-7.32 (m, 4H), 3.13 (s, 3H); LC-MS: m/z 294.05 [M+H]⁺.

N-(4-(amino(4-fluorophenyl)methyl)phenyl)methanesulfonamide (IV)

To a stirred solution of compound IU (1.0 g, 3.4 mmol) in MeOH (10 mL),ammonium acetate (5.25 g, 68.0 mmol), NaBH₃CN (0.59 g, 9.2 mmol) wereadded and the reaction was stirred at 80° C. for 16 h. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with 1N NaOH solution and extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 5%MeOH/DCM to afford IV (0.8 g, 80%) as a light brown semisolid. ¹H NMR(400 MHz, DMSO-d6): δ 7.44-7.34 (m, 4H), 7.17-7.13 (m, 4H), 5.24 (s,1H), 2.95 (s, 3H).

N-(4-(((5-cyanopyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(IW)

To a stirred solution of compound IV (0.8 g, 2.70 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.38 g, 2.70 mmol) in EtOH (15mL), DIPEA (1.5 mL, 8.10 mmol) was added and the reaction was stirred at90° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 5% MeOH/DCM to afford compound IW (0.6 g,56.0%) as an off-white semisolid. LC-MS: m/z 398.15 [M+H]⁺.

N-(4-(((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(IX)

To a stirred solution of compound IW (600 mg, 1.51 mmol) in DMF (15 mL),NaN₃ (491 mg, 7.55 mmol), NH₄Cl (408 mg, 7.55 mmol) and LiCl (80 mg)were added and the reaction was stirred at 100° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 2N HCl solution to pH=2. The precipitated solid was filtered,washed with cold water and dried to afford IX (600 mg, 90.0%) as anoff-white solid. LC-MS: m/z 441.15 [M+H]⁺.

N-(4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(129)

To a stirred solution of compound IX (650 mg, 1.5 mmol) in DCM (15 mL),DFAA (385 mg, 2.2 mmol) was added at 0° C. and the reaction was stirredat RT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with 10%NaHCO₃ solution and the product was extracted with DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to affordcompound 129 (200 mg, 28.0%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 9.69 (s, 1H), 9.16 (d, J=8.8 Hz, 1H), 8.87 (d, J=6.0 Hz,2H), 7.62-7.36 (m, 3H), 7.33-7.31 (m, 2H), 7.15-7.11 (m, 4H), 6.44 (d,J=8.8 Hz, 1H), 2.93 (s, 3H); LC-MS: 491.15 [M+H]⁺. HPLC: 98.91%.

Example 130N-(2-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(130)

N-(2-(4-fluorobenzoyl)phenyl)methanesulfonamide (IZ)

To a stirred solution of (2-aminophenyl)(4-fluorophenyl)methanone (IY,5.0 g, 23.25 mmol) in pyridine (25 mL), mesyl chloride (1.8 mL, 23.25mmol) was added at 0° C. and the reaction was stirred at RT for 4 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with water and the productwas extracted with EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford IZ (3.0 g, 22.0%) as alight brown thick oil.

¹H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 7.78-7.73 (m, 2H), 7.65-7.61(m, 1H), 7.54-7.52 (m, 1H), 7.46-7.43 (m, 1H), 7.39-7.30 (m, 3H), 3.00(s, 3H).

N-(2-(amino(4-fluorophenyl)methyl)phenyl)methanesulfonamide (JA)

To a stirred solution of compound IZ (1.5 g, 5.11 mmol) in MeOH (15 mL),ammonium acetate (7.88 g, 102.3 mmol) and NaBH₃CN (0.82 g, 12.8 mmol)were added and the reaction was stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with IN NaOH solution and theproduct was extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford JA (1.0 g, crude) as a light yellow sticky solid. ¹HNMR (400 MHz, DMSO-d6): δ 7.48-7.21 (m, 4H), 7.19-6.97 (m, 4H), 5.55 (s,1H), 2.80 (s, 3H).

N-(2-(((5-cyanopyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(JB)

To a stirred solution of compound JA (0.5 g, 1.70 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.23 g, 1.70 mmol) in EtOH (10mL), DIPEA (0.89 mL, 8.10 mmol) was added and the reaction was stirredat 90° C. for 8 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 50% EtOAc/hexane to afford compound JB (0.35g, 52.0%) as a light yellow semisolid. LC-MS: m/z 398.10 [M+H]⁺.

N-(2-(((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(JC)

To a stirred solution of compound JB (350 mg, 0.88 mmol) in DMF (7 mL),NaN₃ (171 mg, 2.64 mmol), NH₄Cl (142 mg, 2.64 mmol) and LiCl (37 mg)were added and the reaction was stirred at 100° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 2N HCl solution till pH=2. The precipitated solid was filtered,washed with cold water and dried to afford JC (350 mg, 91.0%) as anoff-white solid. LC-MS: m/z 441.10 [M+H]⁺.

N-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-2,2-difluoro-N-((4-fluorophenyl)(2-(methylsulfonamido)phenyl)methyl)acetamide(JD)

To a stirred solution of compound JC (350 mg, 0.79 mmol) in DCM (5 mL),DFAA (207 mg, 1.19 mmol) was added at 0° C. and the reaction was stirredat RT for 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with 10% MeOH/DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 40% EtOAc/hexane to affordcompound JD (300 mg, 67.0%) as an off-white solid. LC-MS: 569.10 [M+H]⁺.

N-(2-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(130)

To a stirred solution of compound JD (300 mg, 0.52 mmol) in ACN (5 mL),K₂CO₃ (145 mg, 1.05 mmol) was added at 0° C. and the reaction wasstirred at 80° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasfiltered. The filtrate was diluted with water and the product extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30%EtOAc/hexane to afford 130 (50 mg, 20.0%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d6): δ 9.32 (s, 1H), 9.00 (d, J=8.4 Hz, 1H), 8.89 (m,2H), 7.65-7.25 (m, 7H), 7.17-7.13 (m, 2H), 6.98 (d, J=8.8 Hz, 1H), 2.90(s, 3H); LC-MS: 491.15 [M+H]⁺; HPLC: 96.94%.

Example 131N-(2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(131)

1-(4-fluorophenyl)-2-(2-nitrophenyl)ethan-1-one (JF)

To a stirred solution of 2-(2-nitrophenyl)acetic acid (JE, 2.0 g, 11.04mmol) in DCE (10 mL) was added thionyl chloride (1.56 g, 13.25 mmol) at0° C. and the reaction mixture was stirred at 70° C. for 4 h. To theresulting reaction mixture, AlCl₃ (1.5 g, 11.04 mmol) was added followedby fluorobenzene (CV, 10 mL) at 0° C. and the reaction mixture wasstirred at 40° C. for 1 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith ice cold water and the product was extracted with DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 10% EtOAc/hexane to affordcompound JF (0.5 g, 20.0%) as a light brown solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.16-8.10 (m, 3H), 7.74 (t, J=7.4 Hz, 1H), 7.60-7.54 (m,2H), 7.40 (t, J=8.8 Hz, 2H) 4.87 (s, 2H); LC-MS: m/z 260.00 [M+H]⁺.

1-(4-fluorophenyl)-2-(2-nitrophenyl)ethan-1-amine (JG)

To a stirred solution of compound JF (1.3 g, 5.01 mmol) in MeOH (20 mL)was added ammonium acetate (7.7 g, 100.38 mmol) and the reaction mixturewas stirred at RT for 30 min. Then NaBH₃CN (0.8 g, 12.54 mmol) was addedand the reaction mixture was stirred at 80° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was diluted with EtOAc and washed withsaturated NaHCO₃ solution. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound JG(0.8 g, 61.5%) as a light yellow sticky solid. ¹H NMR (400 MHz,DMSO-d6): δ 7.88 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.44 (t,J=7.6 Hz, 1H), 7.31 (t, J=7.2 Hz, 3H), 7.11 (t, J=8.8 Hz, 2H), 4.20 (t,J=7.0 Hz, 1H), 3.25-3.15 (m, 2H); LC-MS: m/z 260.80 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-(2-nitrophenyl)ethyl)amino)pyrimidine-5-carbonitrile(JH)

To a stirred solution of compound JG (0.8 g, 3.07 mmol) in EtOH (15 mL)was added DIPEA (1.6 mL, 9.23 mmol) followed by2-chloropyrimidine-5-carbonitrile (5, 0.51 g, 3.69 mmol) and thereaction mixture was stirred at 90° C. for 8 h. The progress of reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 30% EtOAc/hexane toafford compound JH (0.7 g, 63.0%) as an off white solid. ¹H NMR (400MHz, DMSO-d6): δ 8.53 (brs, 1H), 8.47 (brs, 1H), 7.90 (d, J=8.0 Hz, 1H),7.55 (t, J=7.4 Hz, 1H), 7.48-7.37 (m, 4H), 7.12 (t, J=8.8 Hz, 2H),5.44-5.40 (m, 1H), 3.41-3.35 (m, 1H), 3.28-3.22 (m, 1H); LC-MS: m/z364.10 [M+H]⁺.

2-((2-(2-aminophenyl)-1-(4-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(JI)

To a stirred solution of compound JH (0.7 g, 1.92 mmol) in IPA (10 mL)was added NH₄Cl (0.52 g, 9.64 mmol) dissolved in water (10 mL) followedby iron powder (0.54 g, 9.64 mmol) at RT and the reaction mixture wasstirred at 80° C. for 8 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure. Theresidue was suspended in water and the product was extracted with EtOAc.The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound JI (0.5 g, 78.0%)as a light brown solid which was used as such for the next step. ¹H NMR(400 MHz, DMSO-d6): δ 8.81 (d, J=8.4 Hz, 1H), 8.58 (d, J=2.8 Hz, 2H),7.45-7.42 (m, 2H), 7.13-7.08 (m, 2H), 6.87-6.82 (m, 2H), 6.59 (d, J=8.0Hz, 1H), 6.40-6.37 (m, 1H), 5.32-5.28 (m, 1H), 4.94 (s, 2H), 3.03-2.97(m, 1H), 2.86-2.81 (m, 1H); LC-MS: m/z 334.40 [M+H]⁺.

N-(2-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(JJ)

To a stirred solution of compound JI (0.05 g, 0.15 mmol) in DCM (2 mL)was added pyridine (0.035 g, 0.45 mmol) followed by mesyl chloride (0.02g, 0.18 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for2 h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was quenched with water and theproduct was extracted with EtOAc. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30-50%EtOAc/hexane to afford compound JJ (0.03 g, 48.5%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 8.83 (d, J=8.8 Hz,1H), 8.60-8.55 (m, 2H), 7.44-7.41 (m, 2H), 7.28-7.23 (m, 2H), 7.18-7.06(m, 4H), 5.39-5.33 (s, 1H), 3.24-3.10 (m, 2H), 2.99 (s, 3H).

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(JK)

To a stirred solution of compound JJ (0.3 g, 0.73 mmol) in DMF (5 mL)was added NaN₃ (0.14 g, 2.18 mmol), NH₄Cl (0.12 g, 2.18 mmol) followedby LiCl (0.03 g, 0.73 mmol) and the reaction mixture was stirred at 100°C. for 16 h. Progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 1N HCl solution. The precipitated solid was filtered and driedunder vacuum to yield compound JK (0.3 g, 90.6%) as an off white solid.¹H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.79 (s, 1H), 8.40 (d, J=8.4Hz, 1H), 7.51-7.48 (m, 2H), 7.33-7.28 (m, 2H), 7.21-7.09 (m, 4H),5.40-5.38 (m, 1H), 3.42-3.31 (brs, 2H), 3.21 (d, J=6.8 Hz, 2H), 3.04 (s,3H); LC-MS: m/z 455.50 [M+H]⁺.

N-(2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(131)

To a stirred solution of compound JK (0.3 g, 0.66 mmol) in DCM (5 mL)was added DFAA (0.17 g, 0.99 mmol) at 0° C. and the reaction was stirredat RT for 8 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with 10% MeOH-DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography using 40-50% EtOAc/hexane to afford 131 (0.1 g, 30.0%) asan off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 8.81-8.77(m, 3H), 7.62-7.37 (m, 3H), 7.32-7.25 (m, 2H), 7.20-7.08 (m, 4H),5.45-5.39 (m, 1H), 3.33-3.16 (m, 2H), 3.04 (s, 3H); LC-MS: m/z 505.10[M+H]⁺, HPLC: 99.60%.

Example 132N-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(132)

1-(4-fluorophenyl)-2-(3-nitrophenyl)ethan-1-one (JM)

To a stirred solution of 2-(3-nitrophenyl)acetic acid (JL, 5.0 g, 27.60mmol) in DCE (20 mL) was added thionyl chloride (5.01 g, 42.51 mmol) at0° C. and the reaction mixture was stirred at 80° C. for 1 h. To theresulting reaction mixture, AlCl₃ (4.0 g, 30.36 mmol) was added at 0° C.followed by fluorobenzene (CV, 3.9 g, 41.41 mmol) and the reactionmixture was stirred at 60° C. for 2 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was quenched withice cold water and the product was extracted with DCM. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 12% EtOAc/hexane to afford compound JM (4.0 g,56.0%) as a white solid.

2-(3-aminophenyl)-1-(4-fluorophenyl)ethan-1-one (JN)

To a stirred solution of compound JM (3.0 g, 11.58 mmol) in IPA:water(1:1, 30 mL) was added NH₄Cl (3.1 g, 57.91 mmol) followed by iron powder(3.2 g, 57.91 mmol) at RT and the reaction mixture was stirred at 80° C.for 3 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wassuspended in water and the product was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography using 50-60% EtOAc/hexane to afford compound JN(1.8 g, 68.0%) as a light brown liquid. ¹H NMR (400 MHz, DMSO-d6): δ8.10-8.07 (m, 2H), 7.33 (t, J=9.0 Hz, 2H), 6.93 (t, J=7.4 Hz, 1H),6.45-6.36 (m, 3H), 5.02 (s, 2H), 4.15 (s, 2H); LC-MS: m/z 230.20 [M+H]⁺.

N-(3-(2-(4-fluorophenyl)-2-oxoethyl)phenyl)methanesulfonamide (JO)

To a stirred solution of compound JN (2.3 g, 10.04 mmol) in pyridine (30mL) was added mesyl chloride (2.3 g, 20.08 mmol) at 0° C. and thereaction mixture was stirred at 0° C. for 1 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas quenched with water and the product was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 15% EtOAc/hexane to afford compound JO (3.2g, 95.5%) as a brown liquid. ¹H NMR (400 MHz, DMSO-d6): δ 9.71 (brs,1H), 8.14-8.10 (m, 2H), 7.36 (t, J=8.8 Hz, 2H), 7.27 (t, J=7.6 Hz, 1H),7.10-7.07 (m, 2H), 7.00 (d, J=7.2 Hz, 1H), 4.38 (s, 2H), 2.96 (s, 3H);LC-MS: m/z 308.05 [M+H]⁺.

N-(3-(2-amino-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide (JP)

To a stirred solution of compound JO (1.0 g, 3.25 mmol) in MeOH (20 mL)was added ammonium acetate (5.0 g, 65.14 mmol) at 0° C. and the reactionmixture was stirred 0° C. for 1 h. To the resulting reaction mixture,NaBH₃CN (0.55 g, 8.79 mmol) was added and the reaction mixture wasstirred at 80° C. for 8 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas quenched with 10% NaOH solution and the product was extracted withEtOAc. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 60-100% EtOAc/hexane to affordcompound JP (0.75 g, 75.0%) as a brown liquid. LC-MS: m/z 309.00 [M+H]⁺.

N-(3-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(JQ)

To a stirred solution of compound JP (0.75 g, 2.43 mmol) in EtOH (20 mL)was added DIPEA (1.8 mL, 9.74 mmol) followed by2-chloropyrimidine-5-carbonitrile (AF, 0.41 g, 2.92 mmol) and thereaction mixture was stirred at 90° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound JQ (0.5 g, 50.0%) as a yellow liquid. ¹HNMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.96 (d, J=8.8 Hz, 1H), 8.59 (s,2H), 7.45-7.42 (m, 2H), 7.21-7.09 (m, 4H), 7.03-6.96 (m, 2H), 5.31-5.25(m, 1H), 3.14-3.08 (m, 1H), 3.02-3.01 (m, 1H), 2.87 (s, 3H); LC-MS: m/z412.15 [M+H]⁺.

N-(3-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(JR)

To a stirred solution of compound JQ (0.45 g, 1.09 mmol) in DMF (12 mL)was added NaN₃ (0.36 g, 5.47 mmol), NH₄Cl (0.30 g, 5.47 mmol) followedby LiCl (0.1 g) and the reaction mixture was stirred at 100° C. for 16h. Progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice water and acidified with 1NHCl solution. The precipitated solid was filtered and dried under vacuumto yield compound JR (0.4 g, 80.5%) as a brown liquid. LC-MS: m/z 455.15[M+H]⁺.

N-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-2,2-difluoro-N-(1-(4-fluorophenyl)-2-(3-(methylsulfonamido)phenyl)ethyl)acetamide(JS)

To a stirred solution of compound JR (0.4 g, 0.88 mmol) in DCM (15 mL)was added DFAA (0.31 g, 1.76 mmol) at 0° C. and the reaction was stirredat RT for 16 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography using 36%EtOAc/hexane to afford compound JS (0.185 g, 42.0%) as a light brownsolid. LC-MS: m/z 583.35 [M+H]⁺.

N-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(132)

To a stirred solution of compound JS (0.18 g, 0.31 mmol) in ACN (10 mL)was added K₂CO₃ (0.43 g, 3.09 mmol) and the reaction was stirred at 80°C. for 5 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was cooled to RT andthe solids were filtered. The filtrate was concentrated under reducedpressure. The residue was diluted with water and the product wasextracted with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography using 25-30%EtOAc/hexane to afford 132 (0.06 g, 38.5%) as an off white solid. ¹H NMR(400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.89 (d, J=8.8 Hz, 1H), 8.78 (d,J=11.6 Hz, 2H), 7.63-7.37 (m, 3H), 7.22-7.12 (m, 4H), 7.05 (d, J=7.6 Hz,1H), 6.98 (d, J=8.0 Hz, 1H), 5.38-5.32 (m, 1H), 3.16-3.11 (m, 1H),3.04-2.99 (m, 1H), 2.87 (s, 3H); LC-MS: m/z 505.20 [M+H]⁺; HPLC: 95.24%.

Example 133N-(4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(133)

1-(4-fluorophenyl)-2-(4-nitrophenyl)ethan-1-one (JU)

To a stirred solution of 2-(4-nitrophenyl)acetic acid (JT, 5.0 g, 27.60mmol) in DCE (30 mL) was added thionyl chloride (5.01 g, 42.51 mmol) at0° C. and the reaction mixture was stirred at 80° C. for 3 h. To theresulting reaction mixture, fluorobenzene (CV, 3.9 g, 41.41 mmol) wasadded at 0° C. followed by AlCl₃ (4.0 g, 30.36 mmol) portion wise andthe reaction mixture was stirred at 60° C. for 3 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was cooled to RT, quenched with dilute HCl and washedwith EtOAc. The aqueous layer was basified with 10% NaOH solution andthe product was extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 8%EtOAc/hexane to afford compound JU (3.6 g, 24.0%) as a white solid. ¹HNMR (400 MHz, DMSO-d6): δ 8.19 (d, J=8.8 Hz, 2H), 8.16-8.13 (m, 2H),7.54 (d, J=8.0 Hz, 2H), 7.39 (t, J=8.8 Hz, 2H), 4.62 (s, 2H); LC-MS: m/z257.95 [M−H]⁺.

2-(4-aminophenyl)-1-(4-fluorophenyl)ethan-1-one (JV)

To a stirred solution of compound JU (3.4 g, 13.12 mmol) in IPA:water(1:1, 40 mL) was added NH₄Cl (3.5 g, 65.63 mmol) followed by iron powder(3.7 g, 65.63 mmol) at RT and the reaction mixture was stirred at 80° C.for 3 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. Water was added to theresidue and the product was extracted with EtOAc. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography using 40% EtOAc/hexane to afford compound JV (3.0 g,99.8%) as a yellow liquid. ¹H NMR (400 MHz, DMSO-d6): δ 8.09-8.06 (m,2H), 7.32 (t, J=8.8 Hz, 2H), 6.89 (d, J=7.6 Hz, 2H), 6.47 (d, J=8.0 Hz,2H), 4.95 (brs, 2H), 4.12 (s, 2H); LC-MS: m/z 230.00 [M+H]⁺.

N-(4-(2-(4-fluorophenyl)-2-oxoethyl)phenyl)methanesulfonamide (JW)

To a stirred solution of compound JV (3.0 g, 13.10 mmol) in pyridine (20mL) was added mesyl chloride (2.0 mL, 26.20 mmol) at −10° C. and thereaction mixture was stirred at 0° C. for 1 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas quenched with water and the product was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 28% EtOAc/hexane to afford compound JW (3.2g, 80.0%) as a brown semi solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.67 (brs,1H), 8.14-8.10 (m, 2H), 7.36 (t, J=8.8 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H),7.14 (d, J=8.4 Hz, 2H), 4.34 (s, 2H), 2.96 (s, 3H); LC-MS: m/z 307.75[M+H]⁺.

N-(4-(2-amino-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide (JX)

To a stirred solution of compound JW (1.0 g, 3.25 mmol) in MeOH (20 mL)was added ammonium acetate (5.0 g, 65.14 mmol) at 0° C. and the reactionmixture was stirred at 0° C. for 1 h. To the resulting reaction mixture,NaBH₃CN (0.55 g, 8.79 mmol) was added and the reaction mixture wasstirred at 80° C. for 8 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas quenched with 10% NaOH solution and the product was extracted withEtOAc. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 70% EtOAc/hexane to affordcompound JX (0.3 g, 22.5%) as a brown liquid. LC-MS: m/z 292.15 [M−16]⁺.

N-(4-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(JY)

To a stirred solution of compound JX (0.3 g, 0.97 mmol) in EtOH (8 mL)was added DIPEA (0.7 mL, 3.89 mmol) followed by2-chloropyrimidine-5-carbonitrile (AF, 0.16 g, 1.16 mmol) and thereaction mixture was stirred at 90° C. for 16 h. The progress ofreaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound JY (0.22 g, 55.0%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.93 (d, J=8.8 Hz, 1H),8.59-8.57 (m, 2H), 7.46-7.43 (m, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.13 (t,J=8.8 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 5.31-5.25 (m, 1H), 3.09-2.94 (m,2H), 2.91 (s, 3H); LC-MS: m/z 412.10 [M+H]⁺.

N-(4-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(JZ)

To a stirred solution of compound JY (0.2 g, 0.48 mmol) in DMF (10 mL)was added NaN₃ (0.16 g, 2.43 mmol) and NH₄Cl (0.13 g, 2.43 mmol)followed by LiCl (0.06 g) and the reaction mixture was stirred at 100°C. for 16 h. Progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 1N HCl solution. The precipitated solid was filtered off and driedunder vacuum to yield compound JZ (0.13 g, 59.0%) as a light brownsolid. ¹H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 8.77-8.72 (m, 2H),8.56 (d, J=8.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.12(t, J=8.8 Hz, 3H), 7.06 (d, J=8.4 Hz, 2H), 5.28-5.27 (m, 1H), 3.11-3.05(m, 1H), 2.99-2.94 (m, 1H), 2.88 (s, 3H); LC-MS: m/z 455.10 [M+H]⁺.

N-(4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(133)

To a stirred solution of compound JZ (0.13 g, 0.28 mmol) in DCM (10 mL)was added DFAA (0.15 g, 0.85 mmol) at 0° C. and the reaction was stirredat RT for 16 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture cooled to 0° C.,quenched with water and the product was extracted with DCM. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford crude compound which was purified by silicagel column chromatography using 48% EtOAc/hexane to afford 133 (0.05 g,35.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H),8.85-8.74 (m, 3H), 7.62-7.36 (m, 3H), 7.25 (d, J=8.4 Hz, 2H), 7.14 (t,J=8.8 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 5.34-5.28 (m, 1H), 3.11-3.05 (m,1H), 3.01-2.96 (m, 1H), 2.89 (s, 3H); LC-MS: m/z 505.20 [M+H]⁺; HPLC:88.78%.

Example 134N-(2-cyclopropoxy-l-(2,4-difluorophenyl)ethyl)-5-(5-(difluoromethyl)-)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(134A and 134B)

2-amino-2-(2,4-difluorophenyl)acetonitrile (KB)

A mixture of 2,4-difluorobenzaldehyde (KA, 15.0 g, 105.63 mmol), TMS-CN(13.1 g, 132.04 mmol) and catalytic ZnI₂ (0.15 g) was stirred at RT for2 h. Then 7M NH₃ in MeOH (200 mL) was added and the reaction mixture wasstirred at 50° C. for 3 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was cooledto RT and concentrated under reduced pressure to yield compound KB (17.0g, crude) as a brown solid, which was used as such for the nextreaction.

tert-butyl(cyano(2,4-difluorophenyl)methyl)carbamate (KC)

To a stirred solution of compound KB (17.0 g, 101.19 mmol) inMeOH:Acetone (1:1, 200 mL) was added β-Cyclodextrine (11.5 g, 10.12mmol) followed by di-tert-butyl dicarbonate (24.2 g, 111.31 mmol) at RTand the reaction mixture was stirred at RT for 12 h. After completion ofthe reaction, the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. Water was added to the residue andthe product was extracted with EtOAc. The combined organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield the crude compound whichwas purified by silica gel column chromatography eluting with 5%EtOAc/hexane to afford compound KC (13.0 g, 48.1%) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.36 (brs, 1H), 7.64-7.58 (m, 1H),7.40-7.34 (m, 1H), 7.22-7.18 (m, 1H), 5.98 (d, J=7.6 Hz, 1H), 1.40 (s,9H).

tert-butyl(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamate (KD)

To a stirred solution of compound KC (13.0 g, 48.51 mmol) in DMSO (100mL) was added K₂CO₃ (26.1 g, 194.04 mmol) followed by H₂O₂(22 mL, 194.04mmol, 30% in water) at 10° C. and the reaction mixture was stirred at RTfor 7 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with icewater and the white precipitate was filtered. The solid was washed withwater and hexane and dried under high vacuum to afford compound KD (11.0g, crude) which was used as such for the next step. ¹H NMR (400 MHz,DMSO-d6): δ 7.46-7.37 (m, 3H), 7.23-7.18 (m, 2H), 7.07 (t, J=8.6 Hz,1H), 5.28 (d, J=8.0 Hz, 1H), 1.37 (s, 9H).

2-((tert-butoxycarbonyl)amino)-2-(2,4-difluorophenyl)acetic Acid (KE)

To a stirred solution of compound KD (11.0 g, 38.46 mmol) in MeOH (100mL) was added NaOH (3.1 g, 76.92 mmol) in water (50 mL) at RT and thereaction mixture was stirred at 75° C. for 12 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with water and washed with EtOAc. The aqueouslayer was treated with 2N HCl to pH 3 and the product was extracted withEtOAc. The combined organic layer was washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound KE (10.5 g, 95.1%) as an off white solid. LC-MS: m/z 188.0[M+1-boc]⁺.

2-amino-2-(2,4-difluorophenyl)acetic Acid Hydrochloride (KF)

To a stirred solution of compound KE (10.0 g, 34.84 mmol) in EtOAc (100mL) was added 4M HCl in EtOAc (50 mL) at RT and the reaction mixture wasstirred at RT for 4 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue wastriturated with diethyl ether to afford compound KF (9.0 g, crude) as awhite sticky solid. LC-MS: m/z 187.95 [M+H]⁺.

2-amino-2-(2,4-difluorophenyl)ethan-1-ol (KG)

To a stirred solution of compound KF (9.0 g, 40.36 mmol) in THF (250 mL)was added NaBH₄ (5.9 g, 161.44 mmol) at 0° C. followed by dropwiseaddition of 12 (10.2 g, 40.36 mmol) in THF (50 mL) and the reactionmixture was stirred at 70° C. for 15 h. After completion of thereaction, the reaction mixture was quenched with MeOH and concentratedunder reduced pressure. Then 2N KOH solution was added to the residueand the mixture was stirred at RT for 2 h. The product was extractedwith DCM. The combined organic layer was washed with water and brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toyield compound KG (5.0 g, crude) as a colorless sticky liquid which wasused as such for the next step. LC-MS: m/z 174.00 [M+H]⁺.

2-((1-(2,4-difluorophenyl)-2-hydroxyethyl)amino)pyrimidine-5-carbonitrile(KH)

To a stirred solution of compound KG (5.0 g, 28.90 mmol) in EtOH (50 mL)was added 2-chloropyrimidine-5-carbonitrile (AF, 4.0 g, 28.90 mmol) andDIPEA (20.0 mL, 115.6 mmol) in a sealed tube and the reaction mixturewas stirred at 90° C. for 8 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure to yield the crude compoundwhich was purified by silica gel column chromatography using 30%EtOAc/hexane to afford compound KH (2.5 g, 38.5%) as an off white solid.¹H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J=8.4 Hz, 1H), 8.68 (d, J=3.2 Hz,2H), 7.50-7.44 (m, 1H), 7.21-7.15 (m, 1H), 7.07-7.02 (m, 1H), 5.38-5.32(m, 1H), 5.07 (t, J=5.8 Hz, 1H), 3.66-3.58 (m, 2H); LC-MS: m/z 277.00[M+H]⁺.

2-((1-(2,4-difluorophenyl)-2-(vinyloxy)ethyl)amino)pyrimidine-5-carbonitrile(KI)

To a stirred solution of compound KH (1.5 g, 6.64 mmol) in n-butyl vinylether (40 mL), BPhen (0.22 g, 0.66 mmol) was added and argon was purgedthrough 30 min. Then Pd (TFA)₂ (0.22 g, 0.66 mmol) was added and argonwas purged for further 10 min. The reaction mixture was stirred at 70°C. for 7 h in a sealed tube. After completion of the reaction, thereaction mixture was quenched with water and the product was extractedwith EtOAc. The combined organic layer was washed with water and brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toyield the crude compound which was purified by silica gel columnchromatography using 10% EtOAc/hexane to afford compound KI (1.2 g,35.6%) as a pale yellow thick liquid. ¹H NMR (400 MHz, DMSO-d6): δ 9.08(d, J=8.4 Hz, 1H), 8.71 (s, 2H), 7.57-7.51 (m, 1H), 7.27-7.22 (m, 1H),7.13-7.08 (m, 1H), 6.53-6.47 (m, 1H), 5.67-5.61 (m, 1H), 4.25-4.21 (m,1H), 4.03-4.00 (m, 2H), 3.90-3.86 (m, 1H); LC-MS: m/z 303.05 [M+H]⁺.

2-((2-cyclopropoxy-1-(2,4-difluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(KJ)

To a stirred solution of compound KI (0.3 g, 0.95 mmol) in diethyl ether(10 mL) was added Et₂Zn (5.2 mL, 5.23 mmol, 15% in toluene) at RTfollowed by dropwise addition of diiodomethane (1.2 g, 4.75 mmol) andthe reaction mixture was allowed to reflux for 5 h. The progress of thereaction was monitored by TLC and LCMS. After completion of thereaction, the reaction mixture was quenched with 1N HCl and the productwas extracted with DCM. The combined organic layer was washed with waterand brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to yield the crude compound which was purified by silica gelcolumn chromatography using 10% EtOAc/hexane to afford compound KJ(0.023 g, 8.0%) as a yellow sticky solid. LC-MS: m/z 317.15 [M+H]⁺.

N-(2-cyclopropoxy-1-(2,4-difluorophenyl)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(KK)

To a stirred solution of compound KJ (0.07 g, 0.23 mmol) in DMF (3 mL)was added NaN₃ (0.075 g, 1.16 mmol) and NH₄Cl (0.061 g, 1.16 mmol)followed by LiCl (0.01 g, 0.23 mmol) and the reaction mixture wasstirred at 100° C. for 12 h. Progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was quenched with icewater and acidified with 1N HCl solution and the product was extractedwith 15% MeOH-DCM. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to yield compound KK(0.07 g, crude) as a brown sticky liquid which was used as such for thenext reaction. LC-MS: m/z 360.15 [M+H]⁺.

N-(2-cyclopropoxy-1-(2,4-difluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(134)

To a stirred solution of compound KK (0.06 g, 0.17 mmol) in DCM (5 mL)was added DFAA (0.1 mL) at 0° C. and the reaction was stirred at RT for24 h. The progress of reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was quenched with aqueous NaHCO₃solution and extracted with DCM. Organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford crude compoundwhich was purified by silica gel column chromatography using 10%EtOAc/hexane to afford racemic 134 (0.022 g, 32.5%) as a yellow stickysolid.

Chiral Preparative HPLC Details for 134A and 134B:

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (YMC Chiralart Cellulose-SC, 250×20mm, 5μ; Mobile Phase: n-Hexane: Isopropyl alcohol (95:5)+0.1% NH₃; Flowrate: 20.0 mL/min) to obtain 134A (2.9 mg) and 134B (3.0 mg).

134A: ¹H NMR (400 MHz, CD3OD): δ 8.89 (s, 2H), 7.49-7.43 (m, 1H),7.30-7.04 (m, 1H), 6.98-6.89 (m, 2H), 5.65 (t, J=6.2 Hz, 1H), 3.81 (d,J=6.4 Hz, 2H), 3.40-3.36 (m, 1H), 1.32-1.28 (m, 1H), 0.54-0.43 (m, 4H);LC-MS: m/z 410.25 [M+H]⁺; HPLC: 99.22%: C-HPLC: 99.47% (RT: 12.99).

134B: ¹H NMR (400 MHz, CD3OD): δ 8.89 (s, 2H), 7.49-7.43 (m, 1H),7.30-7.04 (m, 1H), 6.98-6.89 (m, 2H), 5.65 (t, J=6.4 Hz, 1H), 3.81 (d,J=6.4 Hz, 2H), 3.40-3.38 (m, 1H), 1.31-1.27 (m, 1H), 0.54-0.43 (m, 4H);LC-MS: m/z 410.25 [M+H]⁺; HPLC: 98.62%: C-HPLC: 96.36% (RT: 14.64).

Example 137(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide(137(+))

tert-butyl(2-(2,4-difluorophenyl)-2-oxoethyl)carbamate (KL)

To a stirred solution of compound GL (60.0 g, 0.29 mol) in DCM (1 L) wasadded triethylamine (162 mL, 1.16 mol) at 0° C. and the reaction mixturewas stirred for 15 min. To the resulting reaction mixture, di-tert-butyldicarbonate (94.8 g, 0.43 mol) was added and the reaction mixture wasstirred at RT for 6 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith water and the product was extracted with DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography using 10-20% EtOAc/hexane to afford compound KL (40.0 g,51.0%) as an off white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.07-8.01 (m,1H), 7.00 (t, J=7.8 Hz, 1H), 6.91 (t, J=8.8 Hz, 1H), 5.48 (brs, 1H),4.56 (s, 2H), 1.47 (s, 9H). LC-MS: m/z 171.90 [M+1-boc]⁺.

tert-butyl(2-amino-2-(2,4-difluorophenyl)ethyl)carbamate (KM)

To a stirred solution of compound KL (40.0 g, 0.15 mol) in MeOH (500 mL)was added ammonium acetate (227.3 g, 2.95 mol) and the reaction mixturewas stirred at RT for 30 min. To the resulting reaction mixture, NaBH₃CN(23.1 g, 0.37 mol) was added and the reaction mixture was stirred at 80°C. for 16 h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was quenched withsaturated NaHCO₃ solution and the product was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford compound KM (20.0 g, 50.0%) as a lightbrown thick liquid. ¹H NMR (400 MHz, DMSO-d6): δ 7.56-7.51 (m, 1H),7.13-7.08 (m, 1H), 7.06-7.01 (m, 1H), 6.82 (t, J=5.6 Hz, 1H), 4.13 (t,J=6.4 Hz, 1H), 3.11-2.99 (m, 2H), 1.92 (s, 2H), 1.32 (s, 9H). LC-MS: m/z273.05 [M+H]⁺.

tert-butyl(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)carbamate(KN)

To a stirred solution of compound KM (10.0 g, 0.04 mol) and2-chloropyrimidine-5-carbonitrile (7, 5.6 g, 0.04 mol) in EtOH (150 mL)was added DIPEA (20.3 mL, 0.11 mol) and the reaction mixture was stirredat 90° C. for 15 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude residue was dissolved in EtOAc and washedwith water and brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography using 0-2% MeOH/DCM to affordcompound KN (10.0 g, 72.5%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.72-8.67 (m, 3H), 7.49-7.43 (m, 1H), 7.19-7.14 (m, 1H),7.04-6.97 (m, 2H), 5.45-5.41 (m, 1H), 3.35-3.26 (m, 2H), 1.30 (s, 9H);LC-MS: m/z 376.20 [M+H]⁺; HPLC: 99.43%.

Chiral Preparative HPLC Details for KN(+):

The enantiomers were separated by chiral preparative high performanceliquid chromatography (Chiralpak IA, 250×30 mm, 5μ; Mobile Phase:n-Hexane: Isopropyl alcohol (85:15)+0.1% NH₃; Flow rate: 30.0 mL/min) toobtain KN(+) (3.047 g) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6):δ 8.75-8.68 (m, 3H), 7.50-7.44 (m, 1H), 7.17 (t, J=9.8 Hz, 1H),7.06-6.99 (m, 2H), 5.45-5.41 (m, 1H), 3.39-3.25 (m, 2H), 1.30 (s, 9H);LC-MS: m/z 376.10 [M+H]⁺; HPLC: 97.74%; C-HPLC: 99.64% (RT-6.58).

2-((2-amino-1-(2,4-difluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile.TFAsalt (KO)

To a stirred solution of compound KN(+) (0.6 g, 1.6 mmol) in DCM (10 mL)was added TFA (3 mL) at 0° C. and the reaction mixture was stirred at RTfor 2 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure to yield solid compound which was washed with diethylether and dried under vacuum to afford compound KO (TFA salt, 0.6 g,crude) as an off white solid which was used as such for the nextreaction. LC-MS: m/z 275.95 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(KP)

To a stirred solution of compound KO (0.6 g, 1.54 mmol) in DCM (10 mL)was added triethyl amine (0.54 mL, 3.85 mmol) followed by mesyl chloride(0.15 mL, 1.85 mmol) at 0° C. and the reaction mixture was stirred at 0°C. for 2 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using15-20% EtOAc/hexane to afford compound KP (0.3 g, 53.0%) as a brownthick liquid. ¹H NMR (400 MHz, DMSO-d6): δ 8.77 (d, J=8.4 Hz, 1H), 8.71(s, 2H), 7.57-7.51 (m, 1H), 7.31 (t, J=6.0 Hz, 1H), 7.24-7.19 (m, 1H),7.11-7.07 (m, 1H), 5.49-5.44 (m, 1H), 3.37-3.29 (m, 2H), 2.85 (s, 3H);LC-MS: m/z 354.20 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide(KQ)

To a stirred solution of compound KP (0.3 g, 0.85 mmol) in ACN (5 mL)was added dry K₂CO₃ (0.17 g, 1.27 mmol) followed by methyl iodide (0.14g, 1.02 mmol) in a sealed tube and the reaction mixture was stirred at90° C. for 16 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography elutingwith 15-20% EtOAc/hexane to afford compound KQ (0.27 g, 86.8%) as an offwhite solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J=8.8 Hz, 1H), 8.72(s, 2H), 7.65-7.60 (m, 1H), 7.23 (t, J=10.0 Hz, 1H), 7.12 (t, J=8.2 Hz,1H), 5.68-5.62 (m, 1H), 3.48-3.42 (m, 2H), 2.83 (s, 3H), 2.79 (s, 3H);LC-MS: m/z 368.20 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide(KR)

To a stirred solution of compound KQ (0.27 g, 0.74 mmol) in DMF (5 mL)was added NaN₃ (0.19 g, 2.94 mmol) and NH₄Cl (0.16 g, 2.94 mmol)followed by LiCl (0.03 g, 0.074 mmol) and the reaction mixture wasstirred at 100° C. for 14 h. Progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was quenched with icewater and acidified with 6N HCl solution to pH 4. The resulting whiteprecipitate was filtered and dried under vacuum to afford compound KR(0.25 g, crude). LC-MS: m/z 411.25 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide(137(+))

To a stirred solution of compound KR (0.25 g, 0.61 mmol) in DCM (10 mL)was added DFAA (0.14 mL, 1.2 mmol) at 0° C. and the reaction was stirredat RT for 16 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound which was purified by silica gelcolumn chromatography using 10-20% EtOAc/hexane to afford 137(+) (0.11g, 39.3%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (brs,2H), 8.77 (d, J=9.2 Hz, 1H), 7.69-7.39 (m, 2H), 7.26-7.21 (m, 1H),7.14-7.10 (m, 1H), 5.75-5.68 (m, 1H), 3.45 (d, J=7.6 Hz, 2H), 2.84 (s,3H), 2.81 (s, 3H); LC-MS: m/z 461.15 [M+H]⁺; HPLC: 95.11%; C-HPLC:95.82% (RT: 8.98); SOR: +24.4, Solvent: Methanol, Path length: 100 mm,Concentration: 100 w/v %.

Example 138(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(138(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(KS)

To a stirred solution of compound KP (0.34 g, 0.96 mmol) in ACN (10 mL),K₂CO₃ (0.397 g, 2.88 mmol) was added at 0° C. and stirred for 10 min. Tothe resulting reaction mixture 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.35 mL, 2.41 mmol) was added and thereaction was stirred at 60° C. for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas diluted with EtOAc and washed with water. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 30-32% EtOAc/hexane to afford KS (0.315 g, 75.0%)as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.78 (d, J=8.8 Hz,1H), 8.73 (s, 2H), 7.59-7.57 (m, 1H), 7.26-7.21 (m, 1H), 7.14-7.11 (m,1H), 5.76-5.75 (m, 1H), 4.17-4.11 (m, 2H), 3.68-3.63 (m, 2H), 3.02 (s,3H); LC-MS: 436.55 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(KT)

To a stirred solution of compound KS (0.31 g, 0.71 mmol) in DMF (10 mL),NaN₃ (0.23 g, 3.57 mmol), NH₄Cl (0.2 g, 3.57 mmol) and LiCl (0.09 g)were added and the reaction was stirred at 100° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was quenched with icewater and acidified with 2N HCl solution to pH=2. The precipitated solidwas filtered, washed with cold water and dried to afford KT (0.3 g,88.0%) as an off white solid. LC-MS: m/z 479.55 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(138(+))

To a stirred solution of compound KT (0.30 g, 0.62 mmol) in DCM (25 mL),DFAA (0.15 mL, 1.21 mmol) was added at 0° C. and the reaction wasstirred at RT for 16 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was dilutedwith DCM and washed with saturated NaHCO₃ solution. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 20-22% EtOAc/hexane to afford 138(+) (0.12g, 44.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (d,J=7.2 Hz, 2H), 8.69 (d, J=8.8 Hz, 1H), 7.64-7.09 (m, 4H), 5.83-5.77 (m,1H), 4.24-4.10 (m, 2H), 3.72-3.61 (m, 2H), 3.02 (s, 3H); LC-MS: 529.60[M+H]⁺; HPLC: 99.86%, C-HPLC: 97.46% (RT: 7.13); SOR:+66.80, Solvent:Methanol, Path length: 100 mm, Concentration: 0.28 w/v %.

Example 139(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide(139(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide(KU)

To a stirred solution of compound KO (0.60 g, 1.54 mmol) in DCM (10 mL),Triethyl amine (0.54 mL, 3.85 mmol) and ethanesulfonyl chloride (0.18 g,1.85 mmol) were added at 0° C. and stirred at RT for 2 h. The progressof the reaction was monitored by TLC. After completion of the reaction,the reaction mixture was diluted with water and the product wasextracted with DCM. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 30%EtOAc/hexane to afford KU (0.3 g, 52.0%) as an off white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.75 (d, J=8.4 Hz, 1H), 8.71 (s, 2H), 7.56-7.06(m, 4H), 5.48-5.42 (m, 1H), 3.35-3.26 (m, 2H), 2.99-2.89 (m, 2H), 1.10(t, J=7.2 Hz, 3H); LC-MS: 368.20 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide(KV)

To a stirred solution of compound KU (0.30 g, 0.80 mmol) in DMF (4 mL),NaN₃ (0.21 g, 3.20 mmol), NH₄Cl (0.18 g, 3.20 mmol) and LiCl (0.004 g)were added and the reaction was stirred at 100° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 6N HCl solution to pH=4. The precipitated solid was filtered,washed with cold water, and dried to afford KV (0.29 g, 86.5%) as an offwhite solid. LC-MS: m/z 411.25 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide(139(+))

To a stirred solution of compound 3 (0.29 g, 0.70 mmol) in DCM (5 mL),DFAA (0.17 mL, 1.40 mmol) was added at 0° C. and the reaction wasstirred at RT for 16 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was dilutedwith water and the product was extracted with DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to afford 139(+)(0.12 g, 43.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.89(d, J=12.0 Hz, 2H), 8.67 (d, J=8.4 Hz, 1H), 7.64-7.07 (m, 5H), 5.54-5.48(m, 1H), 3.40-3.36 (m, 2H), 3.02-2.88 (m, 2H), 1.10 (t, J=7.2 Hz, 3H);LC-MS: 461.20 [M+H]⁺; HPLC: 98.57%, C-HPLC: 99.74% (RT: 12.47);SOR:+82.57, Solvent: methanol, Path length: 100 mm, Concentration:0.2005 w/v %.

Example 140 (+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide(140(+))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide(140(+))

To a stirred solution of 139(+) (0.20 g, 0.43 mmol) in ACN (10 mL),K₂CO₃ (0.18 g, 1.30 mmol), was added at 0° C. and stirred for 15 min. Tothe resulting reaction mixture methyl iodide (0.19 mL, 3.0 mmol) wasadded and the reaction was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with EtOAc and washed with water. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to afford 140(+)(0.125 g, 61.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ8.88 (d, J=3.6 Hz, 2H), 8.75 (d, J=9.2 Hz, 1H), 7.67-7.08 (m, 4H),5.74-5.66 (m, 1H), 3.50 (d, J=7.6 Hz, 2H), 3.01 (q, J=7.4 Hz, 2H), 2.83(s, 3H), 1.09 (t, J=7.4 Hz, 3H); LC-MS: 475.05 [M+H]⁺; HPLC: 99.25%,C-HPLC: 99.37% (RT: 7.53); SOR:+60.56, Solvent: Methanol, Path length:100 mm, Concentration: 0.275 w/v %.

Example 141(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(141(+))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(141(+))

To a stirred solution of 139(+) (0.20 g, 0.43 mmol) in ACN (10 mL),K₂CO₃ (0.18 g, 1.30 mmol) was added at 0° C. and stirred for 10 min. Tothe resulting reaction mixture 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.19 mL, 1.30 mmol) was added and thereaction was stirred at 60° C. for 16 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was diluted with EtOAc and washed with water. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to afford 141(+)(0.065 g, 27.5%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ8.90 (d, J=7.2 Hz, 2H), 8.70 (d, J=9.2 Hz, 1H), 7.64-7.10 (m, 4H),5.83-5.77 (m, 1H), 4.24-4.12 (m, 2H), 3.74-3.58 (m, 2H), 3.24-3.15 (m,2H), 1.12 (t, J=7.4 Hz, 3H); LC-MS: 543.15 [M+H]⁺; HPLC: 99.33%, C-HPLC:98.88% (RT: 6.19); SOR:+78.18, Solvent: methanol, Path length: 100 mm,Concentration: 0.33 w/v %.

Example 142(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide(142(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide(2)

To a stirred solution of compound KO (0.80 g, 2.90 mmol) in DCM (10 mL),triethyl amine (1.21 mL, 8.72 mmol) was added at 0° C. and stirred for30 min. To the resulting reaction mixture, cyclopropanesulfonyl chloride(0.36 g, 2.61 mmol) was added and the reaction was stirred at RT for 1h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was diluted with water and theproduct was extracted with DCM. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 40% EtOAc/hexane to afford KW (0.4 g, 36.0%) as alight yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.76 (d, J=9.6 Hz, 1H),8.70 (s, 2H), 7.56-7.50 (m, 1H), 7.40-7.37 (m, 1H), 7.23-7.17 (m, 1H),7.10-7.05 (m, 1H), 5.50-5.45 (m, 1H), 3.41-3.36 (m, 2H), 0.90-0.86 (m,4H), 1 Proton merged in solvent; LC-MS: 380.10 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide(KX)

To a stirred solution of compound KW (0.40 g, 1.05 mmol) in DMF (10 mL),NaN₃ (0.20 g, 3.16 mmol), NH₄Cl (0.17 g, 3.16 mmol) and LiCl (0.044 g)were added and the reaction was stirred at 100° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 6N HCl solution to pH=2. The precipitated solid was filtered,washed with cold water and dried to afford 3 (0.4 g, 90.0%) as an offwhite solid. LC-MS: m/z 423.10 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide(142(+))

To a stirred solution of compound KX (0.40 g, 0.94 mmol) in DCM (5 mL),DFAA (0.32 g, 1.89 mmol) was added at 0° C. and the reaction was stirredat RT for 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was diluted with waterand the product was extracted with 10% MeOH/DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to afford 142(+)(0.25 g, 56.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.87(d, J=12.4 Hz, 2H), 8.67 (d, J=8.4 Hz, 1H), 7.63-7.06 (m, 5H), 5.57-5.51(m, 1H), 3.43-3.35 (m, 2H), 0.91-0.86 (m, 4H), 1H merged in solventpeak; LC-MS: 473.15 [M+H]⁺; HPLC: 98.94%, C-HPLC: 99.39% (RT: 12.37);SOR:+86.25, Solvent: methanol, Path length: 100 mm, Concentration: 0.25w/v %.

Example 143(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide(143(+))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide(143(+))

To a stirred solution of compound 142(+) (0.18 g, 0.38 mmol) in ACN (5mL), K₂CO₃ (0.16 g, 1.14 mmol) and methyl iodide (0.16 mL, 2.66 mmol)were added at 0° C. and stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was diluted with water and the product wasextracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 40%EtOAc/hexane to afford compound 143(+) (0.09 g, 49.0%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=3.6 Hz, 2H), 8.78 (d,J=8.8 Hz, 1H), 7.67-7.09 (m, 4H), 5.74-5.69 (m, 1H), 3.51 (d, J=8.0 Hz,2H), 2.85 (s, 3H), 2.55-2.54 (m, 1H), 0.92-0.85 (m, 4H); LC-MS: 487.15[M+H]⁺; HPLC: 98.99%; C-HPLC: 99.24% (RT: 6.97); SOR:+61.71, Solvent:methanol, Path length: 50 mm, Concentration: 0.275 w/v %.

Example 144(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(144(+))

To a stirred solution of compound 142(+) (0.15 g, 0.30 mmol) in ACN (5mL), K₂CO₃ (0.13 g, 0.90 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.15 g, 0.60 mmol) were added at RT andstirred at 90° C. for 5 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was dilutedwith water and the product was extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 30% EtOAc/hexane to affordcompound 144(+) (0.053 g, 31.0%) as an off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.90 (d, J=8.4 Hz, 2H), 8.74 (d, J=9.6 Hz, 1H), 7.65-7.11(m, 4H), 5.89-5.83 (m, 1H), 4.28-4.10 (m, 2H), 3.76-3.65 (m, 2H),2.72-2.65 (m, 1H), 1.05-0.64 (s, 4H); LC-MS: 555.20 [M+H]⁺; HPLC:97.90%; C-HPLC: 99.78% (RT: 6.41); SOR:+86.34 Solvent: methanol, Pathlength: 100 mm, Concentration: 0.2005 w/v %.

Example 145(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide(145(+))

To a stirred solution of compound 116(+) (0.17 g, 0.34 mmol) in ACN (10mL), K₂CO₃ (0.14 g, 1.03 mmol) and methyl iodide (0.14 g, 1.03 mmol)were added at 0° C. and stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 5%MeOH/DCM to afford compound 145(+) (0.168 g, 96.5%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=5.2 Hz, 2H), 8.77 (d,J=9.2 Hz, 1H), 7.67-7.05 (m, 5H), 5.74-5.68 (m, 1H), 3.45 (d, J=7.2 Hz,2H), 2.84 (s, 3H), 2.82 (s, 3H); LC-MS: 509.10 [M+H]⁺; HPLC: 99.05%;C-HPLC: 99.15% (RT: 9.11); SOR:+69.87, Solvent: methanol, Path length:100 mm, Concentration: 0.23 w/v %.

Example 146(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(146(+))

To a stirred solution of compound 116(+) (0.23 g, 0.46 mmol) in ACN (10mL), K₂CO₃ (0.19 g, 1.39 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.16 g, 0.69 mmol) were added at RT andstirred at 60° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasdiluted with EtOAc and washed with water. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 5% MeOH/DCM to afford compound 146(+) (0.185 g,69.0%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (d,J=8.8 Hz, 2H), 8.70 (d, J=8.8 Hz, 1H), 7.64-7.06 (m, 5H), 5.84-5.78 (m,1H), 4.25-4.12 (m, 2H), 3.73-3.62 (m, 2H), 3.03 (s, 3H); LC-MS: 577.15[M+H]⁺; HPLC: 97.74%; C-HPLC: 99.44% (RT: 9.20); SOR:+90.86, Solvent:methanol, Path length: 100 mm, Concentration: 0.23 w/v %.

Example 147(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide(147(+))

tert-butyl(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-oxoethyl)carbamate(KY)

To a stirred solution of compound HB (6.3 g, 24.6 mmol) in DCM (100 mL),triethyl amine (10.2 mL, 73.9 mmol) and (Boc)₂O (6.90 mL, 29.5 mmol)were added at 0° C. and stirred at RT for 2 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with DCM and washed with water. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 20% EtOAc/hexane toafford KY (4.8 g, 61.0%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ8.01 (t, J=8.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.92 (d, J=12.0 Hz, 1H),6.76-6.40 (m, 1H), 5.44 (s, 1H), 4.55 (s, 2H), 1.45 (s, 9H); LC-MS: m/z220.0 [M-Boc+H]⁺.

tert-butyl(2-amino-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)carbamate(KZ)

To a stirred solution of compound KY (4.80 g, 15.0 mmol) in MeOH (50mL), ammonium acetate (23.0 g, 300 mmol) and Na(BH₃)CN (2.50 g, 40.5mmol) were added and the reaction was stirred at 60° C. for 6 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with 10% NaOH solution and the product wasextracted with 10% MeOH/DCM. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 2-5% MeOH/DCM to afford KZ (3.48 g, 72.0%) as acolorless oil. ¹H NMR (400 MHz, CD₃OD): δ 7.48-7.44 (m, 1H), 7.04-6.67(m, 4H), 4.24 (t, J=6.6 Hz, 1H), 3.29-3.27 (m, 2H), 1.39 (s, 9H).

tert-butyl(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)carbamate(LA)

To a stirred solution of 2-chloropyrimidine-5-carbonitrile (AF, 1.82 g,13.0 mmol) and compound KZ (3.48 g, 10.8 mmol) in EtOH (50 mL), DIPEA(3.70 mL, 21.7 mmol) was added and the reaction was stirred at 85° C.for 6 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was diluted with EtOAc and washed withwater. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 20% EtOAc/hexane toafford compound LA (3.8 g, 83.0%) as an off white solid. ¹H NMR (400MHz, DMSO-d6): δ 8.72-8.67 (m, 2H), 7.49-7.43 (m, 1H), 7.24-6.98 (m,5H), 5.43-5.41 (m, 1H), 3.35-3.26 (m, 2H), 1.30 (s, 9H). LC-MS: m/z424.15 [M+H]⁺; HPLC: 99.80%.

Chiral Preparative HPLC Details for LA(+):

The enantiomers were separated by chiral preparative high performanceliquid chromatography (Chiralpak IA, 250×30 mm, 5μ; Mobile Phase:n-Hexane: Isopropyl alcohol (85:15)+0.1% NH₃; Flow rate: 30.0 mL/min) toafford LA(+) (1.7 g) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ8.72-8.67 (m, 2H), 7.49-6.87 (m, 6H), 5.44-5.41 (m, 1H), 3.35-3.26 (m,2H), 1.30 (s, 9H). LC-MS: m/z 424.20 [M+H]⁺; HPLC: 98.59%; C-HPLC:99.41% (RT: 7.39); SOR:+65.67, Solvent: methanol, Path length: 10 mm,Concentration: 0.529 w/v %

2-((2-amino-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(LB)

To a stirred solution of compound LA(+) (1.0 g, 2.36 mmol) in DCM (50mL), 30% TFA in DCM (5 mL) was added and the reaction was stirred at RTfor 1 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was evaporated todryness to afford compound LB (TFA salt, 1.25 g, crude) as a light brownsticky solid. LC-MS: 324.05 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)ethanesulfonamide(LC)

To a stirred solution of compound LB (1.25 g, 3.86 mmol) in DCM (100mL), Triethyl amine (1.08 mL, 7.73 mmol) and ethanesulfonyl chloride(0.59 g, 4.64 mmol) were added at 0° C. and stirred at RT for 30 min.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was diluted with DCM and washed withwater. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 5% MeOH/DCM to affordLC (0.9 g, 56.0%) as a light yellow solid. LC-MS: m/z 416.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)ethanesulfonamide(LD)

To a stirred solution of compound LC (0.9 g, 2.16 mmol) in DMF (15 mL),NaN₃ (0.42 g, 6.50 mmol), NH₄Cl (0.36 g, 6.50 mmol) and LiCl (0.091 g)were added and the reaction was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with EtOAc and washed with water. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 2-5% MeOH/DCM to afford compoundLD (0.85 g, 86.0%) as an off white solid. LC-MS: m/z 459.15 [M+H]⁺.

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide(147(+))

To a stirred solution of compound LD (0.85 g, 1.85 mmol) in DCM (10 mL),DFAA (0.64 mL, 5.56 mmol) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was diluted with DCMand washed with saturated NaHCO₃ solution. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 2-5% MeOH/DCM to afford compound 147(+) (0.7 g,74.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d,J=13.2 Hz, 2H), 8.66 (d, J=8.8 Hz, 1H), 7.70-7.00 (m, 6H), 5.12-4.98 (m,1H), 3.35-3.33 (m, 2H), 2.97-2.93 (m, 2H), 1.10 (t, J=7.2 Hz, 3H),LC-MS: 509.15 [M+H]⁺, HPLC: 98.53%; C-HPLC: 99.53% (RT: 10.15);SOR:+80.02, Solvent: methanol, Path length: 100 mm, Concentration: 100w/v %

Example 148(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide(148(+))

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide(148(+))

To a stirred solution of compound 147(+) (0.2 g, 0.39 mmol) in ACN (15mL), K₂CO₃ (0.16 g, 1.18 mmol) and methyl iodide (0.22 g, 1.57 mmol)were added at 0° C. and stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered and the solids were washed with DCM. Thefiltrate was concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 5% MeOH/DCM to affordcompound 148(+) (0.09 g, 44.0%) as an off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.89 (d, J=4.4 Hz, 2H), 8.75 (d, J=8.8 Hz, 1H), 7.67-7.05(m, 5H), 5.75-5.67 (m, 1H), 3.52 (d, J=7.2 Hz, 2H), 3.01 (q, J=7.2 Hz,2H), 2.85 (s, 3H), 1.10 (t, J=7.2 Hz, 3H); LC-MS: 523.20 [M+H]⁺; HPLC:96.92%; C-HPLC: 96.93% (RT: 7.42); SOR: +86.11, Solvent: methanol, Pathlength: 100 mm, Concentration: 100 w/v %.

Example 149(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(149(+))

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(149(+))

To a stirred solution of compound 147(+) (0.25 g, 0.49 mmol) in ACN (10mL), K₂CO₃ (0.20 g, 1.47 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.17 g, 0.73 mmol) were added at 0° C. andstirred at 60° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasdiluted with EtOAc and washed with water. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 5% MeOH/DCM to afford compound 149(+) (0.11 g,38.0%) as sticky colorless solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.91 (d,J=7.6 Hz, 2H), 8.70 (d, J=9.2 Hz, 1H), 7.64-7.06 (m, 5H), 5.84-5.75 (m,1H), 4.27-4.16 (m, 2H), 3.75-3.60 (m, 2H), 3.25-3.14 (m, 2H), 1.13 (t,J=7.2 Hz, 3H); LC-MS: 591.10 [M+H]⁺; HPLC: 98.95%; C-HPLC: 98.69% (RT:6.44); SOR: +77.47, Solvent: methanol, Path length: 100 mm,Concentration: 100 w/v %.

Example 150(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide(150(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)cyclopropanesulfonamide(LE)

To a stirred solution of compound LB (0.55 g, 1.70 mmol) in DCM (50 mL),triethyl amine (0.47 mL, 3.40 mmol) and cyclopropanesulfonyl chloride(0.36 g, 2.55 mmol) were added at 0° C. and stirred at RT for 30 min.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was diluted with DCM and washed withwater. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 5%MeOH/DCM to afford LE (0.45 g, 62.0%) as a light yellow solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.76 (d, J=8.4 Hz, 1H), 8.71 (d, J=1.6 Hz, 2H),7.56-7.02 (m, 5H), 5.51-5.46 (m, 1H), 3.41-3.34 (m, 2H), 0.89-0.86 (m,4H), (1H merged in solvent peak); LC-MS: m/z 428.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)cyclopropanesulfonamide(LF)

To a stirred solution of compound LE (0.45 g, 1.05 mmol) in DMF (10 mL),NaN₃ (0.205 g, 3.16 mmol), NH₄Cl (0.177 g, 3.16 mmol) and LiCl (0.044 g)were added and the reaction was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with EtOAc and washed with water. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound LF (0.45 g,Crude) as a brown sticky solid. LC-MS: m/z 471.20 [M+H]⁺.

N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide(150(+))

To a stirred solution of compound LF (0.45 g, 0.95 mmol) in DCM (25 mL),DFAA (0.33 g, 1.91 mmol) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was diluted with DCMand washed with saturated NaHCO₃ solution. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 2-5% MeOH/DCM to afford compound 150(+) (0.35 g,70.5%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d,J=13.2 Hz, 2H), 8.67 (d, J=8.8 Hz, 1H), 7.64-7.03 (m, 6H), 5.58-5.52 (m,1H), 3.41-3.39 (m, 2H), 0.90-0.88 (m, 4H), (1H merged in solvent);LC-MS: 521.10 [M+H]⁺, HPLC: 98.59%; C-HPLC: 99.17% (RT: 11.19); SOR:+68.59, Solvent: methanol, Path length: 100 mm, Concentration: 100 w/v %

Example 151(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide(151(+))

To a stirred solution of compound 150(+) (0.15 g, 0.28 mmol) in ACN (15mL), K₂CO₃ (0.16 g, 1.15 mmol) and methyl iodide (0.28 g, 2.01 mmol)were added and the reaction was stirred at RT for 16 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through pad of celite and washed with DCM.The filtrate was concentrated under reduced pressure. The crude productwas purified by silica gel column chromatography using 5% MeOH/DCM toafford compound 151(+) (0.09 g, 58.5%) as an off white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.90 (d, J=3.6 Hz, 2H), 8.78 (d, J=9.2 Hz, 1H),7.67-7.05 (m, 5H), 5.75-5.69 (m, 1H), 3.54-3.52 (m, 2H), 2.86 (s, 3H),2.56-2.54 (m, 1H), 0.92-0.86 (m, 4H); LC-MS: 535.15 [M+H]⁺; HPLC:98.74%; C-HPLC: 98.84% (RT: 8.45); SOR:+69.86, Solvent: methanol, Pathlength: 100 mm, Concentration: 0.23 w/v %.

Example 152(+)N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(152(+))

To a stirred solution of compound 150(+) (0.15 g, 0.28 mmol) in ACN (15mL), K₂CO₃ (0.12 g, 0.86 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.10 g, 0.43 mmol) were added at 0° C. andstirred at RT for 16 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was filteredthrough pad of celite and washed with DCM. The organic layer wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 5% MeOH/DCM to afford compound toafford compound 152(+) (0.090 g, 52.0%) as an off white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.90 (d, J=9.2 Hz, 2H), 8.74 (d, J=9.2 Hz, 1H),7.65-7.06 (m, 5H), 5.89-5.83 (m, 1H), 4.29-4.14 (m, 2H), 3.76-3.67 (m,2H), 2.70-2.65 (m, 1H), 1.05-0.92 (m, 4H); LC-MS: 603.10 [M+H]⁺; HPLC:99.25%; C-HPLC: 99.84% (RT: 7.20); SOR: +85.99, Solvent: methanol, Pathlength: 100 mm, Concentration: 0.23 w/v %.

Example 153(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide(153(+))

tert-butyl(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)carbamate (LG)

To a stirred solution of compound HI (5.0 g, 19 mmol) in dichloromethane(50 mL), triethyl amine (8.0 mL, 57 mmol), DMAP (50 mg) andBoc-anhydride (5.10 g, 23.4 mmol) were added at RT and stirred for 16 h.After completion of the reaction, the reaction mixture quenched withwater (30 mL) and extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford LG (12 g, 33%) as an offwhite solid. ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, J=8.8 Hz, 2H), 7.33 (d,J=8.4 Hz, 2H), 5.50 (s, 1H), 4.66 (d, J=3.6 Hz, 2H), 1.49 (s, 9H).

tert-butyl(2-amino-2-(4-(trifluoromethoxy)phenyl)ethyl)carbamate (LH)

To a stirred solution of compound LG (6.0 g, 16.8 mmol) in MeOH (200mL), ammonium acetate (26.0 g, 337 mmol) and NaCNBH₃ (2.85 g, 45 mmol)were added and the reaction was stirred at 60° C. for 8 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was diluted with 10% NaOH solution and theproduct was extracted with EtOAc. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 3% MeOH/DCM to afford LH (10 g, 83.1%) as an offwhite solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.44 (d, J=8.8 Hz, 2H), 7.27(d, J=8.4 Hz, 2H), 6.82 (m, 1H), 3.91 (t, J=6.6 Hz, 1H), 3.12-3.06 (m,1H), 3.01-2.94 (m, 1H), 1.31 (s, 6H), 1.22 (s, 3H); LC-MS: m/z 320.95[M+H]⁺.

tert-butyl(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)carbamate(LI)

To a stirred solution of 2-chloropyrimidine-5-carbonitrile (AF, 3.95 g,28 mmol) and compound LH (7.0 g, 21.8 mmol) in EtOH (50 mL), DIPEA (18.5mL, 109 mmol) was added and the reaction was stirred at 90° C. for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 20% EtOAc/hexane to afford racemic compound LI (8.5g, 91.9%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.79 (d,J=8.4 Hz, 1H), 8.67 (d, J=9.6 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.30 (d,J=7.6 Hz, 2H), 6.99 (m, 1H), 5.22-5.17 (m, 1H), 3.36-3.29 (m, 2H), 1.29(s, 9H). LC-MS: m/z 424.10 [M+H]⁺; HPLC Purity: 98.60%.

Chiral Preparative HPLC Details for LI(+):

The enantiomers were separated by chiral preparative high performanceliquid chromatography (Chiralpak IA, 250×30 mm, 5; Mobile Phase:n-Hexane: Isopropyl alcohol (85:15)+0.1% NH₃; Flow rate: 30.0 mL/min) toafford LI(+) (4.0 g, 43.0%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.78 (d, J=8.0 Hz, 1H), 8.69-8.65 (m, 2H), 7.47-7.45 (m,2H), 7.31-7.29 (m, 2H), 6.99-6.96 (m, 1H), 5.22-5.17 (m, 1H), 3.36-3.29(m, 2H), 1.29 (s, 9H); LC-MS: m/z 424.10 [M+H]⁺; C-HPLC: 99.74% (RT:6.10); SOR: +61.8, Solvent: methanol, Path length: 10 mm, Concentration:0.5 w/v %

2-((2-amino-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidine-5-carbonitrile(LJ)

To a stirred solution of compound LI(+) (2.3 g, 5.4 mmol) in DCM (10mL), 30% TFA in DCM (20 mL) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated toafford compound LJ (2 g, crude) as a light brown thick oil. LCMS: 324.05(M+H).

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(LK)

To a stirred solution of compound LJ (0.65 g, 2.0 mmol) in DCM (10 mL),triethyl amine (0.60 mL, 6.0 mmol) and methanesulfonyl chloride (0.25 g,2.2 mmol) were added at 0° C. and stirred for 45 min. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with water and the product was extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 5%MeOH/DCM to afford LK (0.35 g, 43.0%) as an off white solid. LC-MS: m/z402.15 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide(LL)

To a stirred solution of compound LK (0.3 g, 0.75 mmol) in ACN (5 mL),K₂CO₃ (0.31 g, 2.2 mmol) and methyl iodide (0.3 mL, 5.2 mmol) were addedand the reaction was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with EtOAc and washed with water. Theorganic layer was concentrated under reduced pressure. The crude productwas purified by silica gel column chromatography using 50% EtOAc/hexaneto afford compound LL (0.25 g, 81.0%) as an off white solid. H NMR (400MHz, DMSO-d6): δ 8.84 (m, 1H), 8.69 (s, 2H), 7.56 (d, J=8.8 Hz, 2H),7.35 (d, J=8.4 Hz, 2H), 5.39 (m, 1H), 3.44-3.41 (m, 2H), 2.82 (s, 3H),2.76 (s, 3H); LC-MS: 416.10 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide(LM)

To a stirred solution of compound LL (0.25 g, 0.6 mmol) in DMF (7 mL),NaN₃ (0.19 g, 3.0 mmol), NH₄Cl (0.16 g, 3.0 mmol) and LiCl (0.08 g) wereadded and the reaction was stirred at 100° C. for 16 h. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice water and acidified with 6NHCl solution to pH=2. The precipitated solid was filtered, washed withcold water and dried to afford LM (0.25 g, 91.0%) as a brown solid.LC-MS: m/z 459.20 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide(153(+))

To a stirred solution of compound LM (0.25 g, 0.55 mmol) in DCM (10 mL),DFAA (0.19 g, 1.1 mmol) was added and the reaction was stirred at RT for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withNaHCO3 solution and the product was extracted with DCM. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to affordcompound 153(+) (0.065 g, 23.5%) as an off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.88 (d, J=10.8 Hz, 2H), 8.76 (d, J=8.8 Hz, 1H), 7.64-7.35(m, 5H), 5.49-5.45 (m, 1H), 3.51-3.46 (m, 2H), 2.84 (s, 3H), 2.80 (s,3H); LC-MS: 509.10 [M+H]⁺, HPLC: 99.11%; C-HPLC: 99.31% (RT: 8.91);SOR:+76.10, Solvent: methanol, Path length: 100 mm, Concentration: 100w/v %.

Example 154(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(154(+))

N-(2-((5-cyanopyrimidin2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(LN)

To a stirred solution of compound LK (0.3 g, 0.74 mmol) in ACN (10 mL),K₂CO₃ (0.31 g, 2.24 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.3 mL, 1.9 mmol) were added at 0° C. andstirred at RT for 16 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was dilutedwith EtOAc and washed with water. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 50%EtOAc/hexane to afford compound LN (0.32 g, 89.0%) as an off whitesolid. H NMR (400 MHz, DMSO-d6): δ 8.78 (d, J=8.8 Hz, 1H), 8.72 (d,J=2.8 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 5.53-5.51(m, 1H), 4.18-4.10 (m, 2H), 3.69-3.64 (m, 2H), 3.01 (s, 3H); LC-MS:484.10 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(LO)

To a stirred solution of compound LN (0.32 g, 0.6 mmol) in DMF (10 mL),NaN₃ (0.21 g, 3.3 mmol), NH₄Cl (0.18 g, 3.3 mmol) and LiCl (0.08 g) wereadded and the reaction was stirred at 100° C. for 16 h. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice water and acidified with 6NHCl solution to pH=2. The precipitated solid was filtered, washed withcold water and dried to afford LN (0.25 g, 72.0%) as a brown solid.LC-MS: m/z 527.10 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(154(+))

To a stirred solution of compound LO (0.25 g, 0.48 mmol) in DCM (10 mL),DFAA (0.16 g, 0.95 mmol) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withNaHCO₃ solution and extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 50% EtOAc/hexane to afford compound 154(+) (0.15 g,55.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d,J=16.0 Hz, 2H), 8.70 (d, J=8.8 Hz, 1H), 7.64-7.37 (m, 5H), 5.60-5.55 (m,1H), 4.25-4.10 (m, 2H), 3.74-3.62 (m, 2H), 3.03 (s, 3H); LC-MS: 577.05[M+H]⁺, HPLC: 98.89%; C-HPLC: 99.87% (RT: 5.88); SOR:+97.36, Solvent:methanol, Path length: 100 mm, Concentration: 0.23 w/v %.

Example 155(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide(155(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide(LP)

To a stirred solution of compound LJ (0.65 g, 2.0 mmol) in DCM (10 mL),triethyl amine (0.83 mL, 6.0 mmol) and ethanesulfonyl chloride (0.23 g,1.8 mmol) were added at 0° C. and stirred for 45 min. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and the product was extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 50%EtOAc/hexane to afford LP (0.45 g, 54.0%) as an off white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.80 (d, J=8.8 Hz, 1H), 8.69 (d, J=2.4 Hz, 2H),7.51 (d, J=8.0 Hz, 2H), 7.35-7.27 (m, 3H), 5.24-5.19 (m, 1H), 3.38-3.33(m, 1H), 3.27-3.25 (m, 1H), 2.94-2.88 (m, 2H), 1.06 (t, J=7.2 Hz, 3H),LC-MS: m/z 416.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide(LQ)

To a stirred solution of compound LP (0.45 g, 1.0 mmol) in DMF (10 mL),NaN₃ (0.35 g, 5.4 mmol), NH₄Cl (0.27 g, 5.4 mmol) and LiCl (0.05 g) wereadded and the reaction was stirred at 100° C. for 16 h. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice water and acidified with 1NHCl solution to pH=2. The precipitated solid was filtered, washed withcold water and dried to afford LQ (0.4 g, 81.0%) as an off white solid.LC-MS: m/z 459.0 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide(155(+))

To a stirred solution of compound LQ (0.4 g, 0.87 mmol) in DCM (10 mL),DFAA (0.30 g, 1.7 mmol) was added and the reaction was stirred at RT for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography using 40% EtOAc/hexane to afford compound 155(+) (0.15 g,34.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d,J=14.0 Hz, 2H), 8.71 (d, J=8.8 Hz, 1H), 7.64-7.29 (m, 6H), 5.35-5.26 (m,1H), 3.43-3.29 (m, 2H), 2.96-2.89 (m, 2H), 1.07 (t, J=7.4 Hz, 3H);LC-MS: 509.15 [M+H]⁺, HPLC: 97.71%; C-HPLC: 99.47% (RT: 11.94);SOR:+120.51, Solvent: methanol, Path length: 100 mm, Concentration: 100w/v %

Example 156(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide(156(+))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide(156(+))

To a stirred solution of compound 155(+) (0.1 g, 0.19 mmol) in ACN (2mL), K₂CO₃ (0.08 g, 0.58 mmol) and methyl iodide (0.027 g, 0.19 mmol)were added at 0° C. and stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was diluted with water and the product wasextracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using 40%EtOAc/hexane to afford compound 156(+) (0.055 g, 54.0%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=10.4 Hz, 2H), 8.74 (d,J=8.8 Hz, 1H), 7.64-7.35 (m, 5H), 5.49-5.43 (m, 1H), 3.53-3.49 (m, 2H),3.01 (q, J=7.2 Hz, 2H), 2.83 (s, 3H), 1.10 (t, J=7.4 Hz, 3H); LC-MS:523.15 [M+H]⁺; HPLC: 95.57%; C-HPLC: 95.86% (RT: 7.79); SOR: +73.63,Solvent-methanol, Path length: 100 mm, Concentration: 100 w/v %

Example 157(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(157(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(LR)

To a stirred solution of compound LP (0.4 g, 0.96 mmol) in ACN (10 mL),K₂CO₃ (0.4 g, 2.89 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.56 g, 2.40 mmol) were added at 0° C. andstirred at 60° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasdiluted with water and the product was extracted with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 40% EtOAc/hexane toafford compound LR (0.25 g, 52.0%) as an off white solid. ¹H NMR (400MHz, DMSO-d6): δ 8.78 (d, J=8.8 Hz, 1H), 8.71 (d, J=1.3 Hz, 2H), 7.56(d, J=8.4 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 5.54-5.48 (m, 1H), 4.25-4.07(m, 2H), 3.73-3.58 (m, 2H), 3.21-3.07 (m, 2H), 1.10 (t, J=7.2 Hz, 3H);LC-MS: m/z 498.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(LS)

To a stirred solution of compound LR (0.25 g, 0.50 mmol) in DMF (5 mL),NaN₃ (0.10 g, 1.50 mmol), NH₄Cl (0.08 g, 1.50 mmol) and LiCl (0.021 g)were added and the reaction was stirred at 100° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and acidifiedwith 1N HCl solution to pH=2. The precipitated solid was filtered,washed with cold water and dried to afford LS (0.2 g, 74.0%) as an offwhite solid. LC-MS: m/z 541.20 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(157(+))

To a stirred solution of compound LS (0.2 g, 0.37 mmol) in DCM (2 mL),DFAA (0.10 g, 0.56 mmol) was added and the reaction was stirred at RTfor 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with 10% MeOH/DCM. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography using 50% EtOAc/hexane to affordcompound 157(+) (0.08 g, 37.0%) as an off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.90 (d, J=15.2 Hz, 2H), 8.71 (d, J=8.8 Hz, 1H), 7.61-7.37(m, 5H), 5.58 (m, 1H), 4.30-4.10 (m, 2H), 3.72-3.64 (m, 2H), 3.20-3.14(m, 2H), 1.12 (t, J=7.4 Hz, 3H); LC-MS: 591.05 [M+H]⁺, HPLC: 95.49%;C-HPLC: 99.85% (RT: 7.11); SOR: +71.49, Solvent: methanol, Path length:100 mm, Concentration: 0.23 w/v %

Example 158(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide(158(+))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide(LT)

To a stirred solution of compound LJ (0.7 g, 2.1 mmol) in DCM (10 mL),Et₃N (0.87 mL, 6.3 mmol) and cyclopropanesulfonyl chloride (0.27 g, 1.9mmol) were added at 0° C. and stirred for 45 min. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and the product was extractedwith DCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography using 20%EtOAc/hexane to afford LT (0.45 g, 48.5%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.79 (d, J=8.8 Hz, 1H), 8.70 (s, 2H), 7.52 (d,J=8.4 Hz, 2H), 7.35-7.30 (m, 3H), 5.28-5.23 (m, 1H), 3.47-3.34 (m, 2H),1.23 (s, 1H), 0.87-0.81 (m, 4H). LC-MS: m/z 428.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide(LU)

To a stirred solution of compound LT (0.45 g, 1.0 mmol) in DMF (10 mL),NaN₃ (0.35 g, 5.4 mmol), NH₄Cl (0.27 g, 5.4 mmol) and LiCl (50 mg) wereadded and the reaction was stirred at 100° C. for 16 h. After completionof the reaction, the reaction mixture was quenched with ice water andacidified with 2N HCl solution to pH=2. The precipitated solid wasfiltered, washed with cold water and dried to afford LU (0.4 g, 80.8%)as an off white solid. LC-MS: m/z 471.15 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide(158(+))

To a stirred solution of compound LU (0.4 g, 0.85 mmol) in DCM (10 mL),DFAA (0.29 g, 1.7 mmol) was added and the reaction was stirred at RT for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with water and the productwas extracted with DCM. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel columnchromatography using 40% EtOAc/hexane to afford compound 158(+) (0.4 g,90.9%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.87 (d,J=13.2 Hz, 2H), 8.71 (d, J=8.8 Hz, 1H), 7.64-7.32 (m, 7H), 5.35-5.29 (m,1H), 3.49-3.34 (m, 2H), 0.88-0.86 (m, 4H); LCMS: 521.15 (M+H); HPLC:94.95%; C-HPLC: 99.47% (RT: 12.01).

Example 159(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide(159(+))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide(159(+))

To a stirred solution of compound 158(+) (0.15 g, 0.28 mmol) in ACN (3mL), K₂CO₃ (0.12 g, 0.84 mmol) was added at 0° C. stirred for 15 min,methyl iodide (0.28 g, 2.0 mmol) was added and the reaction was stirredat RT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched with waterand the product was extracted with EtOAc. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography 30% EtOAc/hexane to afford compound 159(+) (0.08 g,52.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d,J=9.2 Hz, 1H), 8.78 (d, J=8.8 Hz, 1H), 7.64-7.35 (m, 5H), 5.48 (q, J=8.4Hz, 1H), 3.59-3.51 (m, 2H), 2.84 (s, 3H), 2.60-2.53 (m, 1H), 1.23-1.22(m, 1H), 0.93-0.84 (m, 4H); LCMS: 535.15 (M+H); HPLC: 98.82%; C-HPLC:99.08% (RT: 7.61).

Example 160(+)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(160(+))

To a stirred solution of compound 158(+) (0.15 g, 0.3 mmol) in ACN (5mL), K₂CO₃ (0.12 g, 0.8 mmol) was added at 0° C. stirred for 15 min,2,2,2-trifluoroethyl trifluoromethanesulfonate (0.2 g, 0.8 mmol) wasadded and the reaction was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with water and the product was extractedwith EtOAc. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography 30%EtOAc/hexane to afford compound 160(+) (0.06 g, 34.2%) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.91 (d, J=14 Hz, 1H), 8.71 (d,J=9.2 Hz, 1H), 7.64-7.37 (m, 5H), 5.65-5.59 (m, 1H), 4.27-4.09 (m, 2H),3.80-3.31 (m, 2H), 2.72-2.66 (m, 1H), 1.23 (m, 1H), 1.06-0.99 (m, 2H),0.94-0.91 (m, 2H); LCMS: 603.25 (M+H); HPLC: 98.17%; C-HPLC: 98.55% (RT:7.20).

Examples 161(+) and 161(−)5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine(161(+) and 161(−))

1-(4-fluorophenyl)-2-(methylthio)ethan-1-one (LV)

To a stirred solution of 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 4.0g, 18.43 mmol) in MeOH (70 mL), NaSMe (2.6 g, 36.86 mmol) was added at0° C. and the reaction mixture was stirred at RT for 3 h. The progressof the reaction was monitored by TLC. After completion of the reaction,the reaction mixture was filtered through celite. The filtrate wasconcentrated under reduced pressure. The residue was dissolved in EtOAcand washed with saturated NaHCO₃ solution. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound LV (3.0 g, 85.0%) as a yellow oil which was used as such forthe next reaction. 1H NMR (400 MHz, CDCl₃): δ 8.04-8.01 (m, 2H), 7.15(t, J=8.4 Hz, 2H), 3.74 (s, 2H), 2.15 (s, 3H).

1-(4-fluorophenyl)-2-(methylsulfonyl)ethan-1-one (LX)

To a stirred solution of compound LV (3.4 g, 18.48 mmol) in DCM (50 mL),mCPBA (12.7 g, 73.91 mmol) was added at 0° C. and the reaction mixturewas stirred at RT for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasfiltered through celite. The organic layer was separated, washed withNaHCO₃ solution, water and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound LX (2.5 g, 64.0%)as an off-white solid which was used as such for the next reaction. ¹HNMR (400 MHz, CDCl₃): δ 8.08-8.05 (m, 2H), 7.21 (t, J=8.6 Hz, 2H), 4.59(s, 2H), 3.16 (s, 3H); LC-MS: m/z 215.00 [M−H]⁺.

1-(4-fluorophenyl)-2-(methylsulfonyl)ethan-1-amine (LY)

To a stirred solution of compound LX (0.5 g, 2.31 mmol) in MeOH (10 mL),ammonium acetate (3.6 g, 46.29 mmol) was added at 0° C. and the reactionmixture was stirred at the same temperature for 30 min. To the resultingreaction mixture NaBH₃CN (0.29 g, 4.62 mmol) was added and stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was diluted with water and basified with10% NaOH solution. The aqueous layer was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to yield the pale yellow solid, which wasdissolved in 4M HCl in EtOAc and stirred for 30 min. The reactionmixture was concentrated under reduced pressure and the residue wastriturated with n-pentane to afford compound LY (0.3 g, 60.0%) as an offwhite solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (brs, 3H), 7.71-7.67 (m,2H), 7.30 (t, J=8.8 Hz, 2H), 4.82 (brs, 1H), 3.99-3.84 (m, 2H), 2.86 (s,3H); LC-MS: m/z 218.20 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)amino)pyrimidine-5-carbonitrile(LZ)

To a stirred solution of compound LY (0.30 g, 1.38 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.19 g, 1.38 mmol) in EtOH (5mL), DIPEA (1.5 mL, 8.29 mmol) was added and the reaction mixture wasstirred at 70° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in EtOAcand then washed with water and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (45%EtOAc/hexane) to afford compound LZ (0.3 g, 68.0%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 9.01 (d, J=8.8 Hz, 1H), 8.71 (d,J=6.8 Hz, 2H), 7.51-7.47 (m, 2H), 7.19 (t, J=8.8 Hz, 2H), 5.71-5.65 (m,1H), 3.82-3.78 (m, 1H), 3.62-3.52 (m, 1H), 2.96 (s, 3H); LC-MS: m/z320.95 [M+H]⁺.

N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(MA)

To a stirred solution of compound LZ (0.3 g, 0.94 mmol) in DMF (10 mL)was added NaN₃ (0.3 g, 4.69 mmol) and NH₄Cl (0.25 g, 4.69 mmol) followedby LiCl (0.06 g) and the reaction mixture was stirred at 100° C. for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was quenched with ice cold water and the productwas extracted with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound MA (0.31 g, 91%) as an off white solid which was used as suchfor the next reaction. ¹H NMR (400 MHz, DMSO-d6): δ 16.65 (brs, 1H),8.86 (s, 2H), 8.64 (d, J=8.8 Hz, 1H), 7.54-7.51 (m, 2H), 7.19 (t, J=8.8Hz, 2H), 5.76-5.68 (m, 1H), 3.84-3.78 (m, 1H), 3.62-3.57 (m, 1H), 2.98(s, 3H); LC-MS: m/z 364.10 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine(161)

To a stirred solution of compound MA (0.3 g, 0.83 mmol) in DCM (10 mL),DFAA (0.29 g, 1.65 mmol) was added at 0° C. and the reaction was stirredat RT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withwater, aqueous layer was extracted with DCM. The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude compound was purified by silica gel column chromatography (40%EtOAc/hexane) to afford racemic 161 (0.2 g, 59%) as an off white solid.

Chiral Preparative HPLC Details for 161(+) and 161(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A; n-Hexane+0.1% DEA/B; DCM:MeOH (1:1); Isocratic Elution 45% B;Flow rate: 30.0 mL/min) to obtain 161(+) (65 mg) and 161(−) (70 mg).

161(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.92 (d, J=8.8 Hz, 1H), 8.89 (s,2H), 7.65-7.39 (m, 3H), 7.20 (t, J=8.8 Hz, 2H), 5.77-5.71 (m, 1H),3.84-3.78 (m, 1H), 3.64-3.60 (m, 1H), 2.98 (s, 3H); LC-MS: m/z 414.10[M+H]⁺; HPLC: 97.12%; C-HPLC: 99.83% (RT: 6.10); SOR: +158.90, Solvent:Methanol, Path length: 10 mm, Concentration: 0.255 w/v %.

161(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.92 (d, J=8.8 Hz, 1H), 8.89 (s,2H), 7.65-7.39 (m, 3H), 7.20 (t, J=8.8 Hz, 2H), 5.77-5.71 (m, 1H),3.84-3.78 (m, 1H), 3.64-3.60 (m, 1H), 2.98 (s, 3H); LC-MS: m/z 414.10[M+H]⁺; HPLC: 96.71%; C-HPLC: 99.25% (RT: 8.01); SOR: −155.76, Solvent:Methanol, Path length: 10 mm, Concentration: 0.25 w/v %.

Examples 162(+) and 162(−)5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(162(+) and 162(Neg))

1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-one (MB)

To a stirred solution of 2,2,2-trifluoroethan-1-ol (6.4 g, 64.51 mmol)in diglyme (70 mL), Cs₂CO₃ (10.5 g, 32.25 mmol) was added and thereaction mixture was stirred at RT for 10 min. To the resulting reactionmixture 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 7.0 g, 32.25 mmol)was added and stirred at RT for 4 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas filtered through celite and washed with diethyl ether. The filtratewas washed with water, then the organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography (30% DCM/hexane) to affordcompound MB (4.8 g, 63.0%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃): δ 7.99-7.95 (m, 2H), 7.18 (t, J=8.6 Hz, 2H), 4.92 (s, 2H), 4.05(q, J=8.66 Hz, 2H); LC-MS: m/z 196.00 [M+H]⁺.

1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-amine (MC)

To a stirred solution of compound MB (2.0 g, 8.47 mmol) in MeOH (30 mL),ammonium acetate (13.0 g, 169.49 mmol) was added followed by portionwise addition of NaBH₃CN (1.4 g, 22.87 mmol) and the reaction mixturewas stirred at 70° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was diluted withwater and basified with 10% NaOH solution. The aqueous layer wasextracted with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. To a stirredsolution of crude compound in EtOAc (5 mL) was added 4M HCl in EtOAc at0° C. The reaction mixture was concentrated under reduced pressure toyield solid compound which was triturated with diethyl ether to affordcompound MC (1.7 g, 85.0%) as an off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.78 (brs, 3H), 7.64-7.60 (m, 2H), 7.29 (t, J=8.8 Hz, 2H),4.57 (t, J=6.0 Hz, 1H), 4.19 (q, J=9.6 Hz, 2H), 4.03-3.98 (m, 1H),3.92-3.88 (m, 1H); LC-MS: m/z 238.10 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)amino)pyrimidine-5-carbonitrile(MD)

To a stirred solution of compound MC (1.0 g, 4.21 mmol) and2-chloropyrimidine-5-carbonitrile (5, 0.59 g, 4.21 mmol) in EtOH (10mL), DIPEA (3.9 mL, 21.09 mmol) was added and the reaction mixture wasstirred at 70° C. for 14 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (17% EtOAc/hexane) to afford compoundMD (1.1 g, 78.5%) as a colorless thick oil. ¹H NMR (400 MHz, DMSO-d6): δ8.93 (d, J=8.8 Hz, 1H), 8.69-8.63 (m, 2H), 7.48-7.44 (m, 2H), 7.16 (t,J=9.2 Hz, 2H), 5.36-5.31 (m, 1H), 4.18-4.07 (m, 2H), 3.90-3.85 (m, 1H),3.80-3.76 (m, 1H); LC-MS: m/z 341.00 [M+H]⁺.

N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(ME)

To a stirred solution of compound MD (1.1 g, 3.23 mmol) in DMF (10 mL),NaN₃ (1.0 g, 16.17 mmol), NH₄Cl (0.87 g, 16.17 mmol), LiCl (0.013 g,0.323 mmol) were added and the reaction mixture was stirred at 90° C.for 14 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice-water, acidifiedwith 1N HCl solution and extracted with EtOAc. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford compound ME (1.0 g, crude) as a brown thick oil whichwas used as such for the next reaction. LC-MS: m/z 384.15 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(162)

To a stirred solution of compound ME (1.0 g, 2.61 mmol) in DCM (10 mL),DFAA (2.2 g, 13.05 mmol) was added at 0° C. and the reaction was stirredat RT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NaHCO₃ solution and the product was extracted with DCM. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography (15% EtOAc/hexane) to afford racemic 162 (0.878 g,78%) as a colorless thick oil.

Chiral Preparative SFC Details for 162(+) and 162(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IA, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH₃ inMethanol; Gradient Elution 10-20% B, 8 min, 20% hold 5 min, 20-30% in 3min; Flow rate: 80.0 mL/min) to obtain 162(+) (100 mg) and 162(−) (100mg).

162(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.88-8.83 (m, 3H), 7.64-7.39 (m,3H), 7.17 (t, J=8.8 Hz, 2H), 5.44-5.38 (m, 1H), 4.19-4.09 (m, 2H),3.92-3.87 (m, 1H), 3.82-3.79 (m, 1H); LC-MS: m/z 434.0 [M+H]⁺; HPLC:98.72%; C-HPLC: 100.00% (RT: 4.16); SOR: +95.67, Solvent: Methanol, Pathlength: 10 mm, Concentration: 0.245 w/v %.

162(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.88-8.83 (m, 3H), 7.64-7.39 (m,3H), 7.17 (t, J=8.8 Hz, 2H), 5.43-5.38 (m, 1H), 4.19-4.09 (m, 2H),3.92-3.87 (m, 1H), 3.82-3.79 (m, 1H); LC-MS: m/z 434.1 [M+H]⁺; HPLC:99.49%; C-HPLC: 99.77% (RT: 4.79); SOR: −70.03, Solvent: Methanol, Pathlength: 10 mm, Concentration: 0.305 w/v %.

Examples 163(+) and 163(−)5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(163(+) and 163(−))

2-(2,4-difluorophenyl)oxirane (MG)

To a stirred solution of 2,4-difluoro-1-vinylbenzene (MF, 30.0 g, 214.29mmol) in DCM (300 mL), NaHCO₃(72.0 g) dissolved in distilled H₂O (30 mL)was added. To the resulting reaction mixture, mCPBA (63 g, 257.15 mmol)was added at 0° C. and the reaction mixture was stirred at RT for 14 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, the reaction mixture was quenched with 10% Na₂SO₄ solutionand stirred for 20 min. The organic layer was separated, washed withsaturated NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography (10% DCM/hexane) to afford compound MG(7.5 g, 22.5%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.20-7.14(m, 1H), 6.95-6.80 (m, 2H), 4.11 (t, J=3.2 Hz, 1H), 3.19-3.17 (m, 1H),2.79-2.77 (m, 1H).

1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-ol (MH)

To a stirred solution of compound MG (7.5 g, 48.08 mmol) in DMF (80 mL),2,2,2-trifluoroethan-1-ol (38.4 g, 384.64 mmol) was added followed byNaO^(t)Bu (1.1 g, 11.44 mmol) and the reaction mixture was stirred at100° C. for 18 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was quenched withwater and extracted with diethyl-ether. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography (20%DCM/hexane) to afford compound MH (5.0 g, 41.0%) as an off-white solid.¹H NMR (400 MHz, CDCl₃): δ 7.57-7.51 (m, 1H), 6.92 (t, J=8.4 Hz, 1H),6.86-6.79 (m, 1H), 5.23-5.21 (m, 1H), 4.01-3.91 (m, 2H), 3.87-3.84 (m,1H), 3.63 (t, J=9.0 Hz, 1H), 2.74 (d, J=3.6 Hz, 1H).

1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-one (MI)

To a stirred solution of compound MH (3.0 g, 11.72 mmol) in DCM (30 mL)and DMSO (10 mL), P₂O₅(4.9 g, 35.16 mmol) was added at 0° C. followed byTEA (8.4 mL, 58.60 mmol) and the reaction mixture was stirred at RT for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withwater. The organic layer was separated, washed with 1N HCl solution,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography (30%DCM/hexane) to afford compound MI (2.5 g, 86.0%) as an off-white solid.¹H NMR (400 MHz, CDCl₃): δ 8.09-8.03 (m, 1H), 7.07-7.02 (m, 1H),6.95-6.90 (m, 1H), 4.845 (d, J=4.0 Hz, 2H), 4.10-4.03 (m, 2H).

1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-amine (MJ)

To a stirred solution of compound MI (2.0 g, 7.87 mmol) in MeOH (30 mL),ammonium acetate (12.1 g, 157.4 mmol) was added and the reaction mixturewas stirred at RT for 10 min. To the resulting reaction mixture NaBH₃CN(1.3 g, 21.25 mmol) was added and the reaction mixture was stirred at70° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The residue was diluted with water and basifiedwith 4M NaOH solution. The aqueous layer was extracted with EtOAc. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was dissolved in 4M HCl inEtOAc and stirred at RT for 15 min. The reaction mixture wasconcentrated under reduced pressure and the residue was triturated withdiethyl ether to afford compound MJ (1.5 g, 75.0%) as an off whitesolid. This compound was used as such for the next reaction. ¹H NMR (400MHz, DMSO-d6): δ 8.86 (brs, 2H), 7.82-7.76 (m, 1H), 7.40-7.34 (m, 1H),7.26-7.22 (m, 1H), 4.69 (t, J=6.4 Hz, 1H), 4.21-4.14 (m, 2H), 4.07-4.03(m, 1H), 3.97-3.93 (m, 1H); LC-MS: m/z 255.95 [M+H]⁺.

2-((1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)amino)pyrimidine-5-carbonitrile(MK)

To a stirred solution of compound MJ (1.0 g, 3.92 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.60 g, 4.31 mmol) in EtOH (20mL), DIPEA (3.6 mL, 19.60 mmol) was added and the reaction mixture wasstirred at 70° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography (15% EtOAc/hexane) to afford compoundMK (1.0 g, 71.5%) as a yellow thick oil. ¹H NMR (400 MHz, DMSO-d6): δ8.97 (d, J=8.4 Hz, 1H), 8.71 (s, 2H), 7.55-7.49 (m, 1H), 7.26-7.21 (m,1H), 7.12-7.07 (m, 1H), 5.59-5.53 (m, 1H), 4.15-4.08 (m, 2H), 3.93-3.88(m, 1H), 3.82-3.78 (m, 1H); LC-MS: m/z 359.10 [M+H]⁺.

N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(ML)

To a stirred solution of compound MK (1.0 g, 2.79 mmol) in DMF (10 mL),NaN₃ (0.91 g, 13.95 mmol), NH₄Cl (0.75 g, 13.95 mmol) and LiCl (0.01 g,0.28 mmol) were added and the reaction mixture was stirred at 100° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residue was quenched with ice water and theproduct was extracted with EtOAc. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordcompound ML (1.1 g, crude) as an off white solid which was used as suchfor the next reaction. LC-MS: m/z 402.10 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(163)

To a stirred solution of compound ML (1.1 g, 2.73 mmol) in DCM (15 mL),DFAA (2.3 g, 13.68 mmol) was added at 0° C. and the reaction was stirredat RT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NaHCO₃ solution and extracted with DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography (20% EtOAc/hexane) to afford racemic 163 (0.85 g, 71%) asa colorless sticky oil.

Chiral Preparative HPLC Details for 163(+) and 163(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A; n-Hexane/B; 0.1% NH3 in Ethanol; Isocratic Elution 18% B; Flowrate: 32.0 mL/min) to obtain 163(+) (100 mg) and 163(−) (100 mg).

163(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.90-8.87 (m, 3H), 7.65-7.39 (m,2H), 7.28-7.22 (m, 1H), 7.13-7.09 (m, 1H), 5.66-5.61 (m, 1H), 4.17-4.10(m, 2H), 3.95-3.90 (m, 1H), 3.85-3.81 (m, 1H); LC-MS: m/z 452.15 [M+H]⁺;HPLC: 99.48%; C-HPLC: 99.84% (RT: 9.73); SOR: +86.19, Solvent: Methanol,Path length: 100 mm, Concentration: 0.26 w/v %.

163(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.90-8.87 (m, 3H), 7.65-7.39 (m,2H), 7.28-7.22 (m, 1H), 7.13-7.09 (m, 1H), 5.66-5.61 (m, 1H), 4.17-4.10(m, 2H), 3.95-3.90 (m, 1H), 3.85-3.81 (m, 1H); LC-MS: m/z 452.10 [M+H]⁺;HPLC: 99.63%; C-HPLC: 99.58% (RT: 12.87); SOR: −85.91, Solvent:Methanol, Path length: 100 mm, Concentration: 0.265 w/v %.

Examples 164(+) and 164(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(164(+) and 164(−))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(164)

To a stirred solution of compound 108 (1.3 g, 2.94 mmol) in ACN (50 mL),K₂CO₃ (1.2 g, 8.82 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.68 g, 2.94 mmol) were added and the reaction mixture was stirred at80° C. for 5 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (1-2% MeOH/DCM)to afford racemic 164 (0.5 g, 33.0%).

Chiral Preparative HPLC Details for 164(+) and 164(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A-n-Hexane+0.1% NH₃; B-Ethanol; Isocratic Elution 65% B; Flowrate: 30.0 mL/min) to obtain 164(+) (195 mg) and 164(−) (190 mg).

164(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=11.6 Hz, 2H), 8.68 (d,J=9.2 Hz, 1H), 7.65-7.39 (m, 3H), 7.21 (t, J=9.0 Hz, 2H), 5.58-5.52 (m,1H), 4.28-4.09 (m, 2H), 3.75-3.72 (m, 1H), 3.63-3.58 (m, 1H), 3.24-3.14(m, 2H), 1.13 (t, J=7.4 Hz, 3H); LC-MS: m/z 525.20 [M+H]⁺; HPLC: 98.31%;C-HPLC: 99.73% (RT: 15.96); SOR: +68.40, Solvent: Methanol, Path length:10 mm, Concentration: 0.305 w/v %.

164(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=11.6 Hz, 2H), 8.68 (d,J=8.8 Hz, 1H), 7.65-7.39 (m, 3H), 7.21 (t, J=8.8 Hz, 2H), 5.58-5.53 (m,1H), 4.28-4.09 (m, 2H), 3.75-3.69 (m, 1H), 3.63-3.58 (m, 1H), 3.24-3.12(m, 2H), 1.13 (t, J=7.2 Hz, 3H); LC-MS: m/z 525.20 [M+H]⁺; HPLC: 98.99%;C-HPLC: 99.25% (RT: 12.01); SOR: −69.27, Solvent: Methanol, Path length:50 mm, Concentration: 0.32 w/v %.

Examples 165(+) and 165(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(165(+) and 165(−))

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(165)

To a stirred solution of compound 110 (1.5 g, 3.30 mmol) in ACN (10 mL),K₂CO₃ (1.4 g, 9.91 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(1.1 g, 4.95 mmol) were added and the reaction mixture was stirred at80° C. for 8 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with EtOAc. Water was added to the filtrate andaqueous layer was extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography (20%EtOAc/hexane) to afford racemic 165 (0.95 g, 54.0%).

Chiral Preparative HPLC Details for 165(+) and 165(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IA, 250×30 mm, 5μ; MobilePhase: A-n-Hexane+0.1% NH₃; B-Isopropyl alcohol; Isocratic Elution 15%B; Flow rate: 32.0 mL/min) to obtain 165(+) (110 mg) and 165(−) (110mg).

165 (+): ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=10.4 Hz, 2H), 8.69 (d,J=9.2 Hz, 1H), 7.65-7.39 (m, 3H), 7.20 (t, J=8.8 Hz, 2H), 5.62-5.56 (m,1H), 4.27-4.09 (m, 2H), 3.78-3.62 (m, 2H), 2.72-2.67 (m, 1H), 1.04-1.01(m, 2H), 0.99-0.93 (m, 2H); LC-MS: m/z 537.15 [M+H]⁺; HPLC: 95.64%;C-HPLC: 99.25% (RT: 12.62); SOR: +67.65, Solvent: Methanol, Path length:10 mm, Concentration: 0.29 w/v %.

165 (−): ¹H NMR (400 MHz, DMSO-d6): δ 8.88 (d, J=10.4 Hz, 2H), 8.69 (d,J=9.2 Hz, 1H), 7.65-7.39 (m, 3H), 7.20 (t, J=8.8 Hz, 2H), 5.62-5.56 (m,1H), 4.27-4.02 (m, 2H), 3.78-3.62 (m, 2H), 3.73-3.67 (m, 1H), 1.07-1.01(m, 2H), 0.99-0.93 (m, 2H); LC-MS: m/z 537.20 [M+H]⁺; HPLC: 97.89%;C-HPLC: 98.71% (RT: 15.21); SOR: −66.00, Solvent: Methanol, Path length:10 mm, Concentration: 0.31 w/v %.

Examples 166(+) and 166(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(166(+) and 166(−))

1-(2,4-dimethoxyphenyl)-N-methylmethanamine (MN)

To a stirred solution of 2,4-dimethoxybenzaldehyde (MM, 20.0 g, 120.48mmol) in MeOH (200 mL), methanamine (33% in MeOH, 15.0 g, 481.90 mmol)was added at 0° C. and the reaction mixture was stirred at RT for 1 h.To the resulting reaction mixture, NaBH₄ (5.5 g, 144.57 mmol) was addedportion wise at 0° C. and the reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was acidified with dilute HCl (200mL) and MeOH was distilled out under reduced pressure. The residue wasdiluted with water and basified with dilute NaOH solution (80 mL). Theaqueous layer was extracted with EtOAc (5×200 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography (50-80% EtOAc/hexane) to afford compound MN (20.0 g,92.0%) as a light yellow liquid. ¹H NMR (400 MHz, DMSO-d6): δ 7.14 (d,J=8.4 Hz, 1H), 6.51 (brs, 1H), 6.47-6.45 (m, 1H), 3.74 (d, J=8.0 Hz,6H), 3.53 (s, 2H), 2.24 (s, 3H); LC-MS: m/z 181.80 [M+H]⁺.

2-((2,4-dimethoxybenzyl)(methyl)amino)-1-(4-fluorophenyl)ethan-1-one(MO)

To a stirred solution of compound MN (15.0 g, 82.87 mmol) in DCM (250mL), triethylamine (11.0 mL, 82.87 mmol) was added at 0° C. followed bydrop wise addition of 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 18.0 g,82.87 mmol) for 30 min and the reaction mixture was stirred at RT for 3h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was diluted with water (500 mL)and extracted with DCM (5×200 mL). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography (40%EtOAc/hexane) to afford compound MO (20.0 g, 76.0%) as a yellow semisolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.06-8.03 (m, 2H), 7.34-7.28 (m,2H), 7.13 (d, J=8.4 Hz, 1H), 6.53-6.46 (m, 2H), 3.74 (brs, 6H), 3.67 (s,2H), 3.53 (s, 2H), 2.16 (s, 3H); LC-MS: m/z 318.20 [M+H]⁺.

N¹-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-N¹-methylethane-1,2-diamine(MP)

To a stirred solution of compound MO (20.0 g, 63.09 mmol) in MeOH (300mL), ammonium acetate (97.2 g, 1261.80 mmol) was added at 0° C. and thereaction mixture was stirred for 20 min. To the resulting reactionmixture, NaBH₃CN (10.9 g, 170.34 mmol) was added portion wise and thereaction mixture was stirred at 70° C. for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The residuewas diluted with water and basified with dilute NaOH solution. Theaqueous layer was extracted with EtOAc (5×200 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography (70-80% EtOAc/hexane) to afford compound MP (14.2 g,71.0%) as a brown liquid. ¹H NMR (400 MHz, DMSO-d6): δ 7.47-7.43 (m,2H), 7.19 (t, J=9.0 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H), 6.54 (brs, 1H),6.48-6.46 (m, 1H), 4.29-4.26 (m, 1H), 3.73 (brs, 6H), 3.60-3.57 (m, 1H),3.39-3.36 (m, 1H), 2.59-2.54 (m, 1H), 2.46-2.40 (m, 1H), 2.16 (s, 3H);LC-MS: m/z 319.15 [M+H]⁺.

2-((2-((2,4-dimethoxybenzyl)(methyl)amino)-1-(4-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(MQ)

To a stirred solution of compound MP (14.0 g, 44.02 mmol) in EtOH (140mL), DIPEA (33.0 mL, 176.08 mmol) and 2-chloropyrimidine-5-carbonitrile(AF, 6.1 g, 44.02 mmol) were added and the reaction mixture was stirredat 80° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography (15-60% EtOAc/hexane) to afford compound MQ (6.5g, 35.0%) as a light yellow semi solid. ¹H NMR (400 MHz, DMSO-d6): δ8.66-8.63 (m, 3H), 7.41-7.38 (m, 2H), 7.12 (t, J=8.8 Hz, 2H), 6.96 (d,J=8.4 Hz, 1H), 6.49 (brs, 1H), 6.40-6.38 (m, 1H), 5.24-5.21 (m, 1H),3.71 (d, J=13.6 Hz, 6H), 3.54-3.51 (m, 1H), 3.43-3.40 (m, 1H), 2.81-2.75(m, 1H), 2.62-2.57 (m, 1H), 2.13 (s, 3H); LC-MS: m/z 422.20 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-(methylamino)ethyl)amino)pyrimidine-5-carbonitrile(MR)

To compound MQ (5.0 g, 11.87 mmol), TFA (10 mL) was added at RT and thereaction mixture was stirred at 60° C. for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudecompound was triturated with diethyl-ether to afford compound MR (4.0 g,crude) as a green solid. LC-MS: m/z 272.00 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(MS)

To a stirred solution of compound MR (2.0 g, 7.38 mmol) in DMF (20 mL),DIPEA (2.85 g, 22.14 mmol), acetic acid (0.89 g, 14.76 mmol) and HATU(3.36 g, 8.85 mmol) were added and the reaction mixture was stirred atRT for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was diluted with water(200 mL) and extracted with EtOAc (5×200 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography (30%EtOAc/hexane) to afford compound MS (1.1 g, 48.0%) as a brown liquid.LC-MS: m/z 314.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(MT)

To a stirred solution of compound MS (1.0 g, 3.19 mmol) in DMF (10 mL),NaN₃ (1.03 g, 15.97 mmol), NH₄Cl (0.86 g, 15.97 mmol), LiCl (0.20 g)were added and the reaction mixture was stirred at 100° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with ice-water, acidified with dilute HClsolution and extracted with EtOAc (3×100 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford compound MT (1.0 g, 88.5%) as a brown liquid which was used assuch for the next reaction. LC-MS: m/z 357.00 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(166)

To a stirred solution of compound MT (1.0 g, 2.80 mmol) in DCM (20 mL),DFAA (2.44 g, 14.04 mmol) was added at 0° C. and the reaction wasstirred at RT for 36 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was dilutedwith water (200 mL) and extracted with DCM (5×200 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography (90% EtOAc/hexane) to afford racemic 166 (0.11 g, 10%) asa yellow solid.

Chiral Preparative SFC Details for 166(+) and 166(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IA, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH₃ inMethanol; Gradient Elution 10-20% B in 2 min, 20% B hold 7 min, 20-25% Bin 3 min, 25-40% B in 4 min, 40% B hold 5 min; Flow rate: 80.0 mL/min)to obtain 166(+) (22 mg) and 166(−) (20 mg).

166(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.90-8.83 (m, 2H), 8.69 (d, J=8.8Hz, 1H), 7.64-7.39 (m, 3H), 7.23-7.14 (m, 2H), 5.53-5.38 (m, 1H),3.72-3.54 (m, 2H), 2.85 (d, J=37.2 Hz, 3H), 1.91 (d, J=6.8 Hz, 3H);LC-MS: m/z 407.15 [M+H]⁺; HPLC: 98.96%; C-HPLC: 100.00% (RT: 5.21); SOR:+96.24, Solvent: Methanol, Path length: 100 mm, Concentration: 0.25 w/v%.

166(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.90-8.83 (m, 2H), 8.69 (d, J=8.8Hz, 1H), 7.64-7.39 (m, 3H), 7.23-7.14 (m, 2H), 5.51-5.40 (m, 1H),3.72-3.54 (m, 2H), 2.85 (d, J=37.2 Hz, 3H), 1.91 (d, J=6.4 Hz, 3H);LC-MS: m/z 407.15 [M+H]⁺; HPLC: 99.66%; C-HPLC: 98.57% (RT: 6.06); SOR:−75.48, Solvent: Methanol, Path length: 100 mm, Concentration: 0.25 w/v%.

Examples 167(+) and 167(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(167(+) and 167(−))

2-((2,4-dimethoxybenzyl)amino)-1 (4-fluorophenyl)ethan-1-one (MV)

To a stirred solution of (2,4-dimethoxyphenyl)methanamine (MU, 13.9 mL,92.16 mmol) in DCM (1 L), 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH,10.0 g, 46.00 mmol) was added at 0° C. slowly over 15 min and thereaction mixture was stirred at RT for 2 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was quenched with saturated NH₄Cl solution and extracted withDCM (2×400 mL). The combined organic layer was washed with saturatedNH₄Cl solution (200 mL) and brine (200 mL) and concentrated underreduced pressure at 40-45° C. The crude compound was dissolved in EtOAc(200 mL) and 4M HCl in EtOAc (14 mL) was added slowly at 0° C. Theorganic phase was concentrated under reduced pressure. The solidcompound was washed with diethyl ether (2×50 mL) to afford compound MV(8.0 g, 57.0%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.26(brs, 2H), 8.11-8.07 (m, 2H), 7.44 (t, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz,1H), 6.61-6.56 (m, 2H), 4.66 (s, 2H), 4.11 (s, 2H), 3.78 (s, 3H), 3.73(s, 3H); LC-MS: m/z 304.10 [M+H]⁺.

N-(2,4-dimethoxybenzyl)-2,2,2-trifluoro-N-(2-(4-fluorophenyl)-2-oxoethyl)acetamide(MW)

To a stirred solution of compound MV (8.0 g, 26.40 mmol) in DCM (160mL), triethylamine (13.4 mL, 79.20 mmol) was added at 0° C. followed byslow addition of trifluoro acetic anhydride (4.4 mL, 31.68 mmol) over 10min and the reaction mixture was stirred at RT for 2 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was quenched with ice water (500 mL) and extracted withDCM (2×500 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound MW(6.5 g, 62.0%) as a sticky light brown semi solid which was used as suchfor the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.12-8.03 (m, 2H),7.41-7.34 (m, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.57-6.49 (m, 2H), 5.02 (s,1H), 4.82 (s, 1H), 4.55 (d, J=28.4 Hz, 2H), 3.74 (s, 3H), 3.64 (d,J=30.0 Hz, 3H); LC-MS: m/z 422.10 [M+Na]⁺.

2-((2,4-dimethoxybenzyl)(2,2,2-trifluoroethyl)amino)-1-(4-fluorophenyl)ethan-1-ol(MX)

To a stirred solution of compound MW (6.5 g, 16.29 mmol) in dry THF (100mL), BH₃-THF solution (IM, 40.7 mL, 40.73 mmol) was added drop wise at0° C. The reaction mixture was stirred at RT for 30 min followed bystirring at 60° C. for 8 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasslowly quenched with MeOH (100 mL) at 0° C. The reaction mixture wasconcentrated under reduced pressure. The crude residue was diluted withsaturated NH₄Cl solution and extracted with DCM. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford compound MX (5.0 g, 79.0%) as a sticky colorless semisolid which was used as such for the next reaction. ¹H NMR (400 MHz,DMSO-d6): δ 7.31-7.27 (m, 2H), 7.11 (t, J=9.2 Hz, 3H), 6.54 (s, 1H),6.47-6.45 (m, 1H), 5.14 (d, J=3.6 Hz, 1H), 4.73-4.71 (m, 1H), 3.77-3.75(m, 8H), 3.44-3.66 (m, 2H), 2.74-2.67 (m, 2H); LC-MS: m/z 410.15[M+Na]⁺.

2-((2,4-dimethoxybenzyl)(2,2,2-trifluoroethyl)amino)-1-(4-fluorophenyl)ethan-1-one (MY)

To a stirred solution of compound MX (5.0 g, 12.91 mmol) in DCM (250mL), DMP reagent (10.9 g, 25.83 mmol) was added at 0° C. and thereaction mixture was stirred at RT for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through celite and washed with DCM. Thefiltrate was concentrated and purified by silica gel columnchromatography (10% EtOAc/hexane) to afford compound MY (4.0 g, 80.0%)as a colorless sticky solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.99-7.95 (m,2H), 7.32 (t, J=8.8 Hz, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.49-6.47 (m, 2H),4.11 (s, 2H), 3.86 (s, 2H), 3.73 (s, 3H), 3.57-3.52 (m, 5H).

N1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-N1-(2,2,2-trifluoroethyl)ethane-1,2-diamine(MZ)

To a stirred solution of compound MY (4.0 g, 10.38 mmol) in MeOH (100mL), ammonium acetate (15.9 g, 207.70 mmol) was added and the reactionmixture was stirred at RT for 20 min. To the resulting reaction mixture,sodium cyanoborohydride (1.6 g, 25.95 mmol) was added portion wise andthe reaction mixture was stirred at 65-75° C. for 12 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudethick solid residue was quenched with ice water (100 mL) and basifiedwith dilute NaOH solution to pH 8-10. The aqueous layer was extractedwith DCM (2×200 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound MZ(3.0 g, 75.0%) as a light brown thick liquid which was used as such forthe next reaction. LC-MS: m/z 387.30 [M+H]⁺.

2-((2-((2,4-dimethoxybenzyl)(2,2,2-trifluoroethyl)amino)-1-(4-fluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(NA)

To a stirred solution of compound MZ (3.0 g, 7.77 mmol) in EtOH (50 mL),DIPEA (3.9 mL, 23.31 mmol) and 2-chloropyrimidine-5-carbonitrile (AF,1.3 g, 9.32 mmol) were added and the reaction mixture was stirred at RTfor 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography (15% EtOAc/hexane) to afford compound NA (2.9 g, 76.0%)as a light brown sticky viscous liquid. ¹H NMR (400 MHz, DMSO-d6): δ8.66-8.62 (m, 3H), 7.36-7.33 (m, 2H), 7.11 (t, J=8.8 Hz, 2H), 7.02 (d,J=8.0 Hz, 1H), 6.50 (s, 1H), 6.40-6.37 (m, 1H), 5.16-5.12 (m, 1H), 3.79(s, 2H), 3.72 (d, J=8.8 Hz, 6H), 3.46-3.37 (m, 1H), 3.06-3.00 (m, 1H),2.92-2.87 (m, 1H) (1H merged in solvent peak).

2-((1-(4-fluorophenyl)-2-((2,2,2-trifluoroethyl)amino)ethyl)amino)pyrimidine-5-carbonitrile(NB)

To compound NA (5.0 g, 10.22 mmol), TFA (10 mL) was added at 0° C. andthe reaction mixture was stirred at RT for 2 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure to obtain darkbrown colored solid. The crude compound was triturated with n-pentane(3×30 mL) to afford compound NB (4.6 g, crude) as gray solid. ¹H NMR(400 MHz, DMSO-d6): δ 8.80 (d, J=8.4 Hz, 1H), 8.70 (d, J=6.4 Hz, 2H),7.45-7.41 (m, 2H), 7.17 (t, J=8.8 Hz, 2H), 5.29-5.24 (m, 1H), 3.80-3.74(m, 1H), 3.62-3.58 (m, 2H), 3.24-3.18 (m, 1H), 3.10-3.06 (m, 1H); LC-MS:m/z 340.00 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(NC)

To a stirred solution of compound NB (2.0 g, 5.90 mmol) in DMF (20 mL),DIPEA (3 mL, 17.69 mmol), acetic acid (0.70 g, 11.79 mmol) and HATU(2.60 g, 7.07 mmol) were added and the reaction mixture was stirred at75-80° C. for 12 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was quenched withice water and extracted with EtOAc (2×100 mL). The combined organiclayer was washed with cold saturated NH₄Cl solution (2×100 mL) and brine(2×100 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by Combiflash (19%EtOAc/hexane) to afford compound NC (0.9 g, 40.0%) as a light brownsticky liquid. ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=9.6 Hz, 1H),8.77-8.68 (m, 2H), 7.58-7.55 (m, 1H), 7.45-7.41 (m, 1H), 7.25-7.17 (m,2H), 5.57-5.47 (m, 1H), 4.33-4.26 (m, 1H), 4.20-4.11 (m, 1H), 3.78-3.72(m, 1H), 3.59-3.53 (m, 1H), 2.70 (s, 3H); LC-MS: m/z 382.05 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(ND)

To a stirred solution of compound NC (0.90 g, 2.36 mmol) in DMF (10 mL),NaN₃ (0.77 g, 11.80 mmol), NH₄Cl (0.64 g, 11.80 mmol), LiCl (0.27 g)were added and the reaction mixture was stirred at 100° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with ice-water (20 mL), acidified with diluteHCl solution to pH 3-4 and extracted with DCM (2×100 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound ND (0.9 g, crude) as a pale yellowsticky solid which was used as such for the next reaction. LC-MS: m/z425.15 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(167)

To a stirred solution of compound ND (0.9 g, 2.00 mmol) in DCM (30 mL),DFAA (2.1 mL, 2.00 mmol) was added at 0° C. over 10 min and the reactionwas stirred at RT for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasquenched with ice water and pH was adjusted to 7 by adding saturatedNaHCO₃ solution. Aqueous layer was extracted with DCM. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by combiflash columnchromatography (35% EtOAc/hexane) to afford racemic 167 (0.5 g, 53%) asan off-white solid.

Chiral Preparative SFC Details for 167(+) and 167(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH3 inMethanol; Gradient Elution 15-25% B over 3 min, 25% B hold 8 min, 25-35%B over 6 min; Flow rate: 80.0 mL/min) to obtain 167(+) (138 mg) and167(−) (134 mg).

167(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.91-8.68 (m, 3H), 7.65-7.40 (m,3H), 7.25-7.17 (m, 2H), 5.65-5.51 (m, 1H), 4.35-4.24 (m, 1H), 4.23-4.11(m, 1H), 3.82-3.54 (m, 2H), 2.05 (d, J=28.8 Hz, 3H); LC-MS: m/z 475.20[M+H]⁺; HPLC: 98.81%; C-HPLC: 99.10% (RT: 6.15); SOR: +106.25, Solvent:Methanol, Path length: 100 mm, Concentration: 0.36 w/v %.

167(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.91-8.68 (m, 3H), 7.65-7.40 (m,3H), 7.25-7.17 (m, 2H), 5.65-5.51 (m, 1H), 4.35-4.11 (m, 2H), 3.82-3.54(m, 2H), 2.05 (d, J=28.8 Hz, 3H); LC-MS: m/z 475.10 [M+H]⁺; HPLC:98.45%; C-HPLC: 98.30% (RT: 6.66); SOR: −103.50, Solvent: Methanol, Pathlength: 100 mm, Concentration: 0.305 w/v %.

Examples 168(+) and 168(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(168(+) and 168(−))

N-(2-(4-fluorophenyl)-2-oxoethyl)cyclopropanecarboxamide (NE)

To a stirred solution of 2-Amino-4-fluoroacetophenone hydrochloride (FZ,5.0 g, 26.45 mmol) in DCM (50 mL), triethylamine (10.5 mL, 79.35 mmol)was added at 0° C. and the reaction mixture was stirred for 10 min. Tothe resulting reaction mixture cyclopropanecarbonyl chloride (2.6 mL,29.10 mmol) was added slowly at 0° C. and stirred at the sametemperature for 30 min followed by at RT for 30 min. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with water and extracted with DCM. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound wastriturated with diethyl ether to afford compound NE (5.0 g, 85%) as anoff white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.44 (t, J=5.4 Hz, 1H),8.08-8.05 (m, 2H), 7.37 (t, J=8.8 Hz, 2H), 4.61 (d, J=6.0 Hz, 2H),1.75-1.69 (m, 1H), 0.69-0.67 (m, 4H); LC-MS: m/z 222.00 [M+H]⁺.

N-(2-amino-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide (NF)

To a stirred solution of compound NE (5.0 g, 22.62 mmol) in MeOH (100mL), ammonium acetate (34.8 g, 452.40 mmol) and NaBH₃CN (3.8 g, 61.00mmol) were added and the reaction mixture was stirred at 70° C. for 12h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was diluted with water and basified with 10% NaOHto pH 8-9. The aqueous layer was extracted with DCM (250 mL×2). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound NF(3.2 g, 63.0%) as a light brown viscous liquid. LC-MS: m/z 223.05[M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(NG)

To a stirred solution of compound NF (3.2 g, 14.40 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 2.2 g, 15.80 mmol) in EtOH (50mL), DIPEA (7.3 mL, 43.20 mmol) was added in a sealed tube and thereaction mixture was stirred at 90° C. for 1 h. The progress of thereaction was monitored by TLC. After completion of the reaction, theprecipitated solid was filtered. The filtrate was concentrated underreduced pressure. The residue was diluted with water and extracted withDCM. The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was triturated with n-pentane to afford compound NG (3.0 g,65.0%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.71 (d,J=2.8 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.34-8.29(m, 1H), 7.35-7.32 (m, 2H), 7.13 (t, J=8.8 Hz, 2H), 5.15-5.09 (m, 1H),3.68-3.56 (m, 2H), 1.60-1.52 (m, 1H), 0.68-0.59 (m, 4H); LC-MS: m/z326.20 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(NH)

To a stirred solution of compound NG (3.0 g, 9.23 mmol) in DMF (30 mL),NaN₃ (2.9 g, 46.15 mmol), NH₄Cl (2.5 g, 46.15 mmol) and LiCl (0.9 g)were added and the reaction mixture was stirred at 100° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with ice-water and acidified with 6N HClsolution to pH 2-3. Aqueous layer was extracted with 10% MeOH/DCM (100mL×3). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford compound NH (2.1 g, 63.0%)as a light brown thick liquid which was used as such for the nextreaction. ¹H NMR (400 MHz, DMSO-d6): δ 16.67 (brs, 1H), 8.82 (d, J=19.6Hz, 2H), 8.41 (d, J=8.0 Hz, 1H), 8.23 (brs, 1H), 7.44-7.40 (m, 2H),7.17-7.12 (m, 2H), 5.23-5.18 (m, 1H), 3.51-3.39 (m, 2H), 1.55-1.49 (m,1H), 0.64-0.60 (m, 4H); LC-MS: m/z 369.15 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(168)

To a stirred solution of compound NH (2.0 g, 5.43 mmol) in DCM (40 mL),DFAA (3.1 mL, 27.17 mmol) was added at 0° C. and the reaction wasstirred at RT for 12 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith cold saturated NaHCO₃ solution. Aqueous layer was extracted withDCM. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byflash column chromatography (40% EtOAc/hexane) to afford racemic 168(1.5 g, 68.0%) as an off white solid.

Chiral Preparative SFC and HPLC Details for 168(+) and 168(−):

The enantiomers were separated in two steps. First, by supercriticalfluid chromatography (Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-CO₂;B-0.1% NH3 in Methanol; Gradient Elution 25-35% B, 1 min, 35% hold 12min, 35-40% in 3 min; Flow rate: 80.0 mL/min) then by normal-phasepreparative high performance liquid chromatography (Chiralpak IG, 250×30mm, 5μ; Mobile Phase: A-n-Hexane+0.1% NH₃; B-Isopropyl alcohol;Isocratic Elution 30% B; Flow rate: 32.0 mL/min) to obtain 168(+) (75mg) and 168(−) (75 mg).

168(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J=17.6 Hz, 2H), 8.71 (d,J=8.0 Hz, 1H), 8.25 (t, J=5.4 Hz, 1H), 7.64-7.39 (m, 3H), 7.16 (t, J=8.8Hz, 2H), 5.27-5.21 (m, 1H), 3.51-3.41 (m, 2H), 1.53-1.48 (m, 1H),0.66-0.58 (m, 4H); LC-MS: m/z 419.00 [M+H]⁺; HPLC: 96.88%; C-HPLC:97.83% (RT: 7.42); SOR: +107.29, Solvent: Methanol, Path length: 10 mm,Concentration: 0.362 w/v %.

168(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J=16.8 Hz, 2H), 8.71 (d,J=8.4 Hz, 1H), 8.24 (t, J=5.6 Hz, 1H), 7.64-7.39 (m, 3H), 7.16 (t, J=9.0Hz, 2H), 5.27-5.21 (m, 1H), 3.50-3.39 (m, 2H), 1.55-1.48 (m, 1H),0.65-0.58 (m, 4H); LC-MS: m/z 419.00 [M+H]⁺; HPLC: 97.44%; C-HPLC:99.57% (RT: 8.10); SOR: −108.59, Solvent: Methanol, Path length: 10 mm,Concentration: 0.284 w/v %.

Examples 169(+) and 169(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(169(+) and 169(−))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(NI)

To a stirred solution of compound MR (2.0 g, 7.38 mmol) in DMF (20 mL),DIPEA (2.85 g, 22.14 mmol), cyclopropanecarboxylic acid (1.27 g, 14.76mmol) and HATU (3.36 g, 8.85 mmol) were added and the reaction mixturewas stirred at RT for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasdiluted with water (200 mL) and extracted with EtOAc (5×200 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography (38% EtOAc/hexane) to afford compound NI (1.24 g, 50.0%)as a brown liquid. LC-MS: m/z 340.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(NJ)

To a stirred solution of compound NI (1.2 g, 3.53 mmol) in DMF (10 mL),NaN₃ (1.15 g, 17.69 mmol), NH₄Cl (0.96 g, 17.69 mmol), LiCl (0.20 g)were added and the reaction mixture was stirred at 100° C. for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with ice-water, acidified with 6N HCl solutionand extracted with EtOAc (5×100 mL). The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford compound NJ (1.2 g, 89.0%) as a light brown liquid which was usedas such for the next reaction. LC-MS: m/z 383.10 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(169)

To a stirred solution of compound NJ (1.2 g, 3.14 mmol) in DCM (30 mL),DFAA (2.73 g, 15.70 mmol) was added at 0° C. and the reaction wasstirred at RT for 36 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was dilutedwith water (200 mL) and extracted with DCM (5×100 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography (60-80% EtOAc/hexane) to afford racemic 169 (0.17 g,12.5%) as a yellow solid.

Chiral Preparative SFC Details for 169(+) and 169(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH₃ inMethanol; Gradient Elution 40% B hold 3 min, 40-45% B in 4 min, 45-50% Bin 2 min, 50% B hold 15 min; Flow rate: 80.0 mL/min) to obtain 169(+)(50 mg) and 169(−) (50 mg).

169(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.89-8.79 (m, 2H), 8.67 (d, J=8.8Hz, 1H), 7.64-7.38 (m, 3H), 7.21-7.14 (m, 2H), 5.54-5.41 (m, 1H),3.94-3.79 (m, 1H), 3.69-3.58 (m, 1H), 3.06 (s, 2H), 2.79 (s, 1H),1.92-1.78 (m, 1H), 0.67-0.54 (m, 4H); LC-MS: m/z 433.20 [M+H]⁺; HPLC:97.39%; C-HPLC: 99.98% (RT: 4.27); SOR: +69.90, Solvent: Methanol, Pathlength: 100 mm, Concentration: 0.25 w/v %.

169(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.89-8.79 (m, 2H), 8.67 (d, J=8.4Hz, 1H), 7.64-7.38 (m, 3H), 7.21-7.14 (m, 2H), 5.54-5.39 (m, 1H),3.93-3.79 (m, 1H), 3.69-3.58 (m, 1H), 3.06 (s, 2H), 2.79 (s, 1H),1.92-1.78 (m, 1H), 0.67-0.54 (m, 4H); LC-MS: m/z 433.15 [M+H]⁺; HPLC:99.62%; C-HPLC: 99.51% (RT: 8.49); SOR: −71.52, Solvent: Methanol, Pathlength: 100 mm, Concentration: 0.25 w/v %.

Examples 170(+) and 170(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(170(+) and 170(−))

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(NK)

To a stirred solution of compound NB (0.50 g, 1.47 mmol) in DCM (20 mL),triethylamine (0.58 mL, 4.42 mmol) was added at 0° C. followed bycyclopropanecarbonyl chloride (0.16 mL, 1.76 mmol) very slowly and thereaction mixture was stirred at the same temperature for 3 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice water and extractedwith DCM. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombiflash (15% EtOAc/hexane) to afford compound NK (0.34 g, 56.0%) as alight brown sticky semi solid. ¹H NMR (400 MHz, DMSO-d6): δ8.86-8.84-8.03 (m, 1H), 8.76-8.67 (m, 2H), 7.55-7.51 (m, 1H), 7.43-7.40(m, 1H), 7.23-7.16 (m, 2H), 5.66-5.47 (m, 1H), 4.58-4.38 (m, 1H),4.18-4.11 (m, 1H), 4.00-3.91 (m, 1H), 3.76-3.56 (m, 1H, 2.12-1.94 (m,1H), 0.81-0.67 (m, 4H); LC-MS: m/z 408.15 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(NL)

To a stirred solution of compound NK (1.30 g, 3.19 mmol) in DMF (10 mL),NaN₃ (1.03 g, 15.90 mmol), NH₄Cl (0.86 g, 15.90 mmol), LiCl (0.40 g)were added and the reaction mixture was stirred at 100° C. for 6 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with ice-water (20 mL), acidified with diluteHCl solution to pH 2-3 and extracted with DCM (2×200 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound NL (1.5 g, crude) as a light brownsticky liquid which was used as such for the next reaction. LC-MS: m/z451.15 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(170)

To a stirred solution of compound NL (1.5 g, 3.33 mmol) in DCM (50 mL),DFAA (3.6 mL, 33.30 mmol) was added at 0° C. over 10 min and thereaction was stirred at RT for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas quenched with ice water (20 mL) and pH was adjusted to 7 by addingsaturated NaHCO₃ solution. Aqueous layer was extracted with DCM. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by combiflashcolumn chromatography (30% EtOAc/hexane) to afford racemic 170 (1.0 g,62.5%) as an off-white solid.

Chiral Preparative SFC Details for 170(+) and 170(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH₃ inMethanol; Gradient Elution 20-30% B over 3 min, 30% B hold 5 min, 30-40%B over 6 min; Flow rate: 80.0 mL/min) to obtain 170(+) (128 mg) and170(−) (118 mg).

170(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 2H), 8.47 (brs, 1H),7.58-7.32 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 5.64 (brs, 1H), 4.30 (brs,2H), 3.92 (brs, 2H), 2.02 (brs, 1H), 0.77 (s, 4H); LC-MS: m/z 501.15[M+H]⁺; HPLC: 99.43%; C-HPLC: 99.73% (RT: 5.75); SOR: +96.58, Solvent:Methanol, Path length: 100 mm, Concentration: 0.48 w/v %.

170(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 2H), 8.46 (brs, 1H),7.58-7.32 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 5.65 (brs, 1H), 4.29 (brs,2H), 3.91 (brs, 2H), 2.02 (brs, 1H), 0.77 (s, 4H); LC-MS: m/z 501.20[M+H]⁺; HPLC: 98.95%; C-HPLC: 98.78% (RT: 7.57); SOR: −87.52, Solvent:Methanol, Path length: 100 mm, Concentration: 0.485 w/v %.

Examples 171(+) and 171(−)N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(171(+) and 171(−))

2-amino-1-(3,4-difluorophenyl)ethan-1-one hydrochloride (NO)

To a stirred solution of 2-chloro-1-(3,4-difluorophenyl)ethan-1-one (NM,10.0 g, 52.46 mmol) in CHCl₃ (100 mL), HMTA (11.0 mL, 78.69 mmol) wasadded and the reaction mixture was stirred at RT for 12 h. Theprecipitated white solid was filtered and dried under high vacuum. Tothe stirred residue in EtOH (25 mL) was added conc. HCl (10 mL) dropwise at 0° C. and the reaction mixture was stirred at RT for 12 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The crude compound was triturated with diethyl ether (50 mL) and hexane(100 mL×2) to afford compound NO (8.1 g, 90.0%) as an off-white solid.LC-MS: m/z 172.15 [M+1]⁺.

tert-butyl(2-(3,4-difluorophenyl)-2-oxoethyl)carbamate (NP)

To a stirred solution of compound NO (8.0 g, 46.78 mmol) in DCM (100mL), triethylamine (25.2 mL, 187.13 mmol) was added followed bydi-tert-butyl dicarbonate (15.3 g, 70.17 mmol) at 0° C. and the reactionmixture was stirred at RT for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas diluted with water (300 mL) and extracted with DCM (200 mL×5). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography (20-50% EtOAc/hexane) to afford compound NP (7.0g, 55.0%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (t, J=9.6Hz, 1H), 7.88 (brs, 1H), 7.65-7.59 (m, 1H), 7.13 (brs, 1H), 4.42 (d,J=6.0 Hz, 2H), 1.39 (s, 9H); LC-MS: m/z 172.00 [M+1-boc]⁺.

tert-butyl(2-amino-2-(3,4-difluorophenyl)ethyl)carbamate (NQ)

To a stirred solution of compound NP (7.0 g, 25.83 mmol) in MeOH (80mL), ammonium acetate (39.8 g, 516.60 mmol) was added at 0° C. and thereaction mixture was stirred for 1 h. To the resulting reaction mixture,NaBH₃CN (4.5 g, 69.74 mmol) was added and the reaction mixture wasstirred at 70° C. for 12 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was basified with 10%NaOH solution (300 mL) and extracted with EtOAc (200 mL×5). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography (10% MeOH/DCM) to afford compound NQ (4.0 g, 37.0%) as abrown liquid. LC-MS: m/z 273.00 [M+H]⁺.

tert-butyl(2-((5-cyanopyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)carbamate(NR)

To a stirred solution of compound NQ (4.0 g, 14.70 mmol) in EtOH (40mL), DIPEA (7.6 g, 58.82 mmol) was added followed by2-chloropyrimidine-5-carbonitrile (AF, 2.0 g, 14.70 mmol) and thereaction mixture was stirred at 80° C. for 12 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (20%EtOAc/hexane) to afford compound NR (1.1 g, 20.0%) as a light yellowsemi solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.73-8.62 (m, 3H), 7.40-7.33(m, 2H), 7.17 (brs, 1H), 6.97 (brs, 1H), 5.19-5.14 (m, 1H), 1.36 (s, 9H)(2H merged in solvent peak); LC-MS: m/z 376.10 [M+H]⁺.

2-((2-amino-1-(3,4-difluorophenyl)ethyl)amino)pyrimidine-5-carbonitrile(NS)

To a stirred solution of compound NR (1.1 g, 2.93 mmol) in DCM (10 mL),TFA (3 mL) was added at 0° C. and the reaction mixture was stirred at RTfor 1 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure to afford compound NS (1.0 g, crude) as a yellow solid.LC-MS: m/z 276.10 [M+H]⁺.

N-(2-((5-cyanopyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(NT)

To a stirred solution of compound NS (1.0 g, 3.63 mmol) in DCM (15 mL),triethyl amine (1.5 g, 14.51 mmol) was added followed by methanesulfonylchloride (0.62 g, 5.45 mmol) at 0° C. and the reaction mixture wasstirred at the same temperature for 30 min. The progress of the reactionwas monitored by TLC. After completion of the reaction, the reactionmixture was diluted with water (200 mL) and extracted with DCM (200mL×5). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (50% EtOAc/hexane) to afford compoundNT (0.51 g, 40.0%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.75(d, J=8.8 Hz, 1H), 8.71 (s, 2H), 7.49-7.37 (m, 2H), 7.27-7.24 (m, 2H),5.23-5.17 (m, 1H), 3.41-3.37 (m, 1H), 3.33-3.26 (m, 1H), 2.86 (s, 3H);LC-MS: m/z 354.00 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(NU)

To a stirred solution of compound NT (0.50 g, 1.41 mmol) in DMF (10 mL),NaN₃ (0.46 g, 7.08 mmol), NH₄Cl (0.38 g, 7.08 mmol), LiCl (0.10 g) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with water (100 mL), acidified with 6N HClsolution and extracted with 10% MeOH/DCM (100 mL×5). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound NU (0.50 g, 90.0%) as a brown liquidwhich was used as such for the next reaction. LC-MS: m/z 396.9 [M+H]⁺.

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(171)

To a stirred solution of compound NU (0.50 g, 1.26 mmol) in DCM (10 mL),DFAA (0.88 g, 5.05 mmol) was added at 0° C. and the reaction was stirredat RT for 12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was diluted with water(100 mL) and extracted with DCM (100 mL×5). The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography (50-70%EtOAc/hexane) to afford racemic 171 (0.4 g, 71.0%) as an off-whitesolid.

Chiral Preparative SFC Details for 171(+) and 171(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH3 inMethanol; Gradient Elution 20-30% B, 3 min, hold 6 min, 30-35% B, 5 min,35-45% B, 4 min, 45-50% B, 4 min; Flow rate: 80.0 mL/min) to obtain171(+) (40 mg) and 171(−) (40 mg).

171(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=12.4 Hz, 2H), 8.66 (d,J=8.0 Hz, 1H), 7.65-7.38 (m, 3H), 7.28 (brs, 2H), 5.30-5.24 (m, 1H),3.43-3.34 (m, 1H), 2.86 (s, 3H) (1H merged in solvent peak); LC-MS: m/z447.15 [M+H]⁺; HPLC: 99.67%; C-HPLC: 98.40% (RT: 8.16); SOR: +70.88,Solvent: Methanol, Path length: 10 mm, Concentration: 0.25 w/v %.

171(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=12.0 Hz, 2H), 8.66 (d,J=8.8 Hz, 1H), 7.65-7.38 (m, 3H), 7.28 (brs, 2H), 5.30-5.24 (m, 1H),3.43-3.35 (m, 1H), 2.86 (s, 3H) (1H merged in solvent peak); LC-MS: m/z447.15 [M+H]⁺; HPLC: 99.68%; C-HPLC: 100.00% (RT: 7.54); SOR: −66.56,Solvent: Methanol, Path length: 10 mm, Concentration: 0.25 w/v %.

Examples 172AN-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172A)

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172A)

To a stirred solution of 171(−) (0.03 g, 0.08 mmol) in ACN (5 mL), K₂CO₃(0.05 g, 0.38 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.12 g, 0.53 mmol) were added and the reaction mixture was stirred at80° C. for 24 h. The progress of the reaction was monitored by TLC andLCMS. After completion of the reaction, the reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography (30%EtOAc/hexane) to afford 172A (0.013 g, 32.5%) as a pale yellow solid. ¹HNMR (400 MHz, DMSO-d6): δ 8.90 (d, J=14.8 Hz, 2H), 8.63 (d, J=8.8 Hz,1H), 7.65-7.40 (m, 3H), 7.32 (brs, 1H), 5.58-5.51 (m, 1H), 4.24-4.10 (m,2H), 3.74-3.59 (m, 2H), 3.04 (s, 3H); LC-MS: m/z 529.15 [M+H]⁺; HPLC:99.58%; C-HPLC: 99.99% (RT: 5.87).

Examples 172BN-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172B)

N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172B)

To a stirred solution of 171(+) (0.05 g, 0.10 mmol) in ACN (5 mL), K₂CO₃(0.07 g, 0.50 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.16 g, 0.71 mmol) were added and the reaction mixture was stirred at80° C. for 24 h. The progress of the reaction was monitored by TLC andLCMS. After completion of the reaction, the reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography (28%EtOAc/hexane) to afford 172B (0.018 g, 34.0%) as a pale yellow solid. ¹HNMR (400 MHz, DMSO-d6): δ 8.90 (d, J=15.2 Hz, 2H), 8.63 (d, J=8.8 Hz,1H), 7.65-7.40 (m, 3H), 7.32 (brs, 1H), 5.58-5.51 (m, 1H), 4.24-4.10 (m,2H), 3.74-3.59 (m, 2H), 3.04 (s, 3H); LC-MS: m/z 529.15 [M+H]⁺; HPLC:99.52%; C-HPLC: 99.31% (RT: 6.33).

Examples 173(+) and 173(−)N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(173(+) and 173(−))

tert-butyl(2-(4-chlorophenyl)-2-oxoethyl)carbamate (NW)

To a stirred solution of 2-Amino-4-chloroacetophenone hydrochloride (NV,5.0 g, 24.27 mmol) in DCM (100 mL), DIPEA (13.0 mL, 72.81 mmol),di-tert-butyl dicarbonate (6.7 mL, 29.12 mmol) were added at 0° C. andthe reaction mixture was stirred at RT for 3 h. The progress of thereaction was monitored by TLC. After completion of the reaction, thereaction mixture was diluted with water. The aqueous layer was extractedwith DCM (250 mL×2). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford compound NW(6.1 g, 94.0%) as an off-white solid which was used as such for the nextreaction. ¹H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J=8.4 Hz, 2H), 7.58 (d,J=8.4 Hz, 2H), 7.07 (t, J=5.6 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 1.36 (s,9H); LC-MS: m/z 169.95 [M+1-boc]⁺.

tert-butyl(2-amino-2-(4-chlorophenyl)ethyl)carbamate (NX)

To a stirred solution of compound NW (5.0 g, 18.58 mmol) in MeOH (125mL), ammonium acetate (28.6 g, 371.60 mmol) NaBH₃CN (3.2 g, 50.18 mmol)were added and the reaction mixture was stirred at 80° C. for 2 h. Theprogress of the reaction was monitored by TLC and LCMS. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The residue was diluted with water and basified with saturatedNaOH solution to pH 9-10. The aqueous layer was extracted with EtOAc(200 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford compound NX (4.9 g,crude) as a yellow semi solid which was used as such for the nextreaction. ¹H NMR (400 MHz, DMSO-d6): δ 7.38-7.25 (m, 5H), 6.82-6.79 (m,1H), 3.86 (t, J=6.6 Hz, 1H), 3.12-3.00 (m, 1H), 2.97-2.91 (m, 1H), 1.34(s, 9H); LC-MS: m/z 271.05 [M+H]⁺.

tert-butyl(2-(4-chlorophenyl)-2-((5-cyanopyrimidin-2-yl)amino)ethyl)carbamate(NY)

To a stirred solution of compound NX (4.9 g, 18.14 mmol) and2-chloropyrimidine-5-carbonitrile (2.5 g, 18.14 mmol) in EtOH (100 mL),DIPEA (9.8 mL, 54.42 mmol) was added and the reaction mixture wasstirred at 80° C. for 12 h. The progress of the reaction was monitoredby TLC and LCMS. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure. The residue was diluted withwater and extracted with EtOAc (200 mL×3). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography(15-30% EtOAc/hexane) to afford compound NY (5.0 g, 74.0%) as anoff-white solid. LC-MS: m/z 374.15 [M+H]⁺.

2-((2-amino-1-(4-chlorophenyl)ethyl)amino)pyrimidine-5-carbonitrile (NZ)

To a stirred solution of compound NY (5.0 g, 13.40 mmol) in DCM (50 mL),TFA (15.5, 134.00 mL) was added at 0° C. and the reaction mixture wasstirred at RT for 16 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The obtained crude was trituratedwith diethyl ether to afford compound NZ (4.0 g, 81.0%) as a yellowsolid. LC-MS: m/z 274.10 [M+H]⁺.

N-(2-(4-chlorophenyl)-2-((5-cyanopyrimidin-2-yl)amino)ethyl)methanesulfonamide(OA)

To a stirred solution of compound NZ (4.0 g, 14.65 mmol) in DCM (100mL), triethyl amine (6.2 mL, 43.95 mmol), methanesulfonyl chloride (7,0.96 mL, 14.65 mmol) were added at 0° C. and the reaction mixture wasstirred at same temperature for 30 min. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas diluted with water and extracted with DCM (200 mL×3). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography (15-30% EtOAc/hexane) to afford compound OA (2.6 g,58.0%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.79 (d,J=8.8 Hz, 1H), 8.71-8.67 (m, 2H), 7.44-7.38 (m, 4H), 7.24 (brs, 1H),5.20-5.16 (m, 1H), 3.39-3.36 (m, 1H), 2.84 (s, 3H) (1H merged in solventpeak); LC-MS: m/z 352.10 [M+H]⁺.

N-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-chlorophenyl)ethyl)methanesulfonamide(OB)

To a stirred solution of compound OA (2.0 g, 5.69 mmol) in DMF (20 mL),NaN₃ (1.85 g, 28.49 mmol), NH₄Cl (1.50 g, 28.49 mmol), LiCl (0.24 g,5.69 mmol) were added and the reaction mixture was stirred at 100° C.for 16 h. The progress of the reaction was monitored by TLC and LCMS.After completion of the reaction, the reaction mixture was diluted withcold water and acidified with 6N HCl solution to pH 4-5. The aqueouslayer was extracted with EtOAc (300 mL×3). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford compound OB (1.9 g, 85.0%) as a yellow solid which was used assuch for the next reaction. ¹H NMR (400 MHz, DMSO-d6): δ 16.75 (brs,1H), 8.84 (brs, 2H), 8.41 (d, J=8.8 Hz, 1H), 7.47-7.36 (m, 4H), 7.24 (t,J=5.8 Hz, 1H), 5.25-5.20 (m, 1H), 3.42-3.38 (m, 2H), 2.84 (s, 3H);LC-MS: m/z 395.10 [M+H]⁺.

N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(173)

To a stirred solution of compound OB (1.9 g, 4.82 mmol) in DCM (30 mL)was added DFAA (1.3 g, 7.23 mmol) at 0° C. and the reaction was stirredat RT for 16 h. The progress of the reaction was monitored by TLC andLCMS. After completion of the reaction, the reaction mixture was dilutedwith water and extracted with DCM (300 mL×3). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude compound was purified by silica gel column chromatography(10-40% EtOAc/hexane) to afford racemic 173 (1.5 g, 70.0%) as anoff-white solid.

Chiral Preparative HPLC Details for 173(+) and 173(−):

The enantiomers were separated by normal-phase preparative highperformance liquid chromatography (Chiralpak IC, 250×30 mm, 5μ; MobilePhase: A-MTBE; B-Ethanol; Isocratic Elution 5% B; Flow rate: 30.0mL/min) to obtain 173(+) (550 mg) and 173(−) (515 mg).

173(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=14.8 Hz, 2H), 8.72 (d,J=8.8 Hz, 1H), 7.65-7.27 (m, 6H), 5.28-5.23 (m, 1H), 3.43-3.37 (m, 1H),2.85 (s, 3H) (1H merged in solvent peak); LC-MS: m/z 445.10 [M+H]⁺;HPLC: 99.89%; C-HPLC: 99.77% (RT: 7.37); SOR: +120.12, Solvent:Methanol, Path length: 10 mm, Concentration: 0.315 w/v %.

173(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=14.8 Hz, 2H), 8.72 (d,J=8.4 Hz, 1H), 7.65-7.39 (m, 5H), 7.27 (brs, 1H), 5.28-5.23 (m, 1H),3.42-3.37 (m, 1H), 2.85 (s, 3H) (1H merged in solvent peak); LC-MS: m/z445.05 [M+H]⁺; HPLC: 99.73%; C-HPLC: 99.78% (RT: 5.78); SOR: −141.62,Solvent: Methanol, Path length: 10 mm, Concentration: 0.32 w/v %.

Example 174(+)N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174(+))

N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174(+))

To a stirred solution of 173(+) (0.25 g, 0.56 mmol) in ACN (10 mL),K₂CO₃ (0.24 g, 1.68 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.20 mL, 1.40 mmol) were added and thereaction mixture was stirred at 80° C. for 12 h. The progress of thereaction was monitored by TLC and LCMS. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with water and extracted with EtOAc (100 mL×2).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (10-30% EtOAc/hexane) to afford 174(+)(0.205 g, 70.0%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ8.89 (d, J=16.0 Hz, 2H), 8.68 (d, J=9.2 Hz, 1H), 7.65-7.39 (m, 5H),5.57-5.51 (m, 1H), 4.25-4.09 (m, 2H), 3.73-3.61 (m, 2H), 3.03 (s, 3H);LC-MS: m/z 527.10 [M+H]⁺; HPLC: 99.47%; C-HPLC: 99.64% (RT: 10.89); SOR:+113.00, Solvent: Methanol, Path length: 10 mm, Concentration: 0.306 w/v%.

Examples 174(−)N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174(−))

N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-(yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174(−))

To a stirred solution of 173(−) (0.20 g, 0.45 mmol) in ACN (10 mL),K₂CO₃ (0.19 g, 1.35 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1, 0.16 mL, 1.12 mmol) were added and thereaction mixture was stirred at 80° C. for 12 h. The progress of thereaction was monitored by TLC and LCMS. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with water and extracted with EtOAc (100 mL×2).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (10-30% EtOAc/hexane) to afford 174(−)(0.126 g, 53.0%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ8.88 (d, J=15.6 Hz, 2H), 8.68 (d, J=9.2 Hz, 1H), 7.64-7.39 (m, 5H),5.56-5.50 (m, 1H), 4.25-4.08 (m, 2H), 3.73-3.60 (m, 2H), 3.02 (s, 3H);LC-MS: m/z 526.90 [M+H]⁺; HPLC: 98.18%; C-HPLC: 99.73% (RT: 9.07); SOR:−81.11, Solvent: Methanol, Path length: 10 mm, Concentration: 0.27 w/v%.

Examples 175(+) and 175(−)5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine(175(+) and 175(−))

1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethan-1-one(OD)

To a stirred solution of 4-(trifluoromethyl)-1H-imidazole (OC, 0.94 g,6.91 mmol) in THF (20 mL), K₂CO₃ (1.14 g, 8.29 mmol) was added and thereaction mixture was stirred at RT for 15 min. To the resulting reactionmixture, 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 1.50 g, 6.91 mmol)was added and the reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was filtered through celite. The filtratewas concentrated under reduced pressure. The crude compound was purifiedby silica gel column chromatography (40% EtOAc/hexane) to affordcompound OD (1.2 g, 67.0%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.14-8.10 (m, 2H), 7.76 (d, J=17.2 Hz, 2H), 7.44 (t, J=8.8Hz, 2H), 5.80 (s, 2H); LC-MS: m/z 272.95 [M+H]⁺.

1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethan-1-amine(OE)

To a stirred solution of compound OD (1.20 g, 4.41 mmol) in MeOH (20mL), ammonium acetate (6.8 g, 88.20 mmol) was added and the reactionmixture was stirred at RT for 20 min. To the resulting reaction mixture,NaBH₃CN (0.75 g, 11.91 mmol) was added and the reaction mixture wasstirred at 80° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wascooled to RT and concentrated under reduced pressure. The residue wasdiluted with 10% NaOH solution and extracted with EtOAc. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound OE (0.8 g, crude) as an off-whitesolid which was used as such for the next reaction. LC-MS: m/z 273.90[M+H]⁺.

2-((1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)amino)pyrimidine-5-carbonitrile(OF)

To a stirred solution of compound OE (0.80 g, 2.93 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 0.45 g, 3.22 mmol) in EtOH (10mL), DIPEA (2.7 mL, 14.65 mmol) was added and the reaction mixture wasstirred at 85° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (40% EtOAc/hexane) to afford compoundOF (0.82 g, 74.5%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ9.01 (d, J=8.8 Hz, 1H), 8.64 (d, J=22.8 Hz, 2H), 7.85 (d, J=18.0 Hz,2H), 7.55-7.47 (m, 2H), 7.24-7.18 (m, 2H), 5.54-5.51 (m, 1H), 4.40-4.32(m, 2H); LC-MS: m/z 376.8 [M+H]⁺.

N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(OG)

To a stirred solution of compound OF (0.82 g, 2.18 mmol) in DMF (10 mL),NaN₃ (0.71 g, 10.90 mmol), NH₄Cl (0.58 g, 10.90 mmol) and LiCl (0.07 g)were added and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue was diluted with 1N HCl and the aqueous layer was extractedwith EtOAc. The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford compound OG (0.65 g,crude) as an off-white solid which was used as such for the nextreaction. LC-MS: m/z 420.05 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine(175)

To a stirred solution of compound OG (0.65 g, 1.55 mmol) in DCM (20 mL),DFAA (0.67 g, 3.87 mmol) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NaHCO₃ solution and the product was extracted with DCM. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography (20% EtOAc/hexane) to afford racemic 175 (0.4 0 g,55.0%) as an off-white solid.

Chiral Preparative SFC Details for 175(+) and 175(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IA, 250×30 mm, 5μ; Mobile Phase: A-CO₂; B-0.1% NH₃ inMethanol; Gradient Elution 10-25% B over 1 min, 25-30% B over 7 min, 30%B hold for 4 min, 30-35% B over 2 min, 35-50% B over 4 min; Flow rate:80.0 mL/min) to obtain 175(+) (60 mg) and 175(−) (60 mg).

175(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.94 (d, J=8.8 Hz, 1H), 8.86 (brs,1H), 8.77 (brs, 1H), 7.88 (d, J=21.6 Hz, 2H), 7.64-7.38 (m, 3H), 7.23(t, J=8.8 Hz, 2H), 5.61-5.55 (m, 1H), 4.44-4.32 (m, 2H); LC-MS: m/z470.15 [M+H]⁺; HPLC: 97.24%; C-HPLC: 98.95% (RT: 5.18); SOR: +70.22,Solvent: Methanol, Path length: 100 mm, Concentration: 0.25 w/v %.

175(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.94 (d, J=9.2 Hz, 1H), 8.86 (brs,1H), 8.76 (brs, 1H), 7.88 (d, J=21.6 Hz, 2H), 7.63-7.38 (m, 3H), 7.23(t, J=8.6 Hz, 2H), 5.61-5.55 (m, 1H), 4.44-4.32 (m, 2H); LC-MS: m/z470.15 [M+H]⁺; HPLC: 97.11%; C-HPLC: 99.35% (RT: 5.85); SOR: −72.35,Solvent: Methanol, Path length: 100 mm, Concentration: 0.25 w/v %.

Examples 176(+) and 176(−)5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine(176(+) and 176(−))

1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one(OI)

To a stirred solution of 4-(trifluoromethyl)-1H-pyrazole (OH, 2.5 g,18.43 mmol) in DMF (50 mL), Cs₂CO₃ (9.0 g, 27.64 mmol) was addedfollowed by 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 4.0 g, 18.43mmol) and the reaction mixture was stirred at RT for 1 h. The progressof the reaction was monitored by TLC. After completion of the reaction,the reaction mixture was diluted with ice water and the aqueous layerwas extracted with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography (40%EtOAc/hexane) to afford compound OI (3.0 g, 60.0%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 8.16-8.12 (m, 2H),7.95 (s, 1H), 7.45 (t, J=8.8 Hz, 2H), 5.95 (s, 2H); LC-MS: m/z 273.00[M+H]⁺.

1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-amine(OJ)

To a stirred solution of compound OI (3.0 g, 11 mmol) in MeOH (150 mL),ammonium acetate (17.0 g, 220 mmol) was added followed by NaBH₃CN (2.1g, 33 mmol) at RT and the reaction mixture was stirred at 80° C. for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, the reaction mixture was cooled to RT and concentratedunder reduced pressure. The residue was diluted with NaHCO₃ solution andextracted with DCM. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography (5% MeOH/DCM) to affordcompound OJ (2.3 g, 76.5%) as an off-white solid. LC-MS: m/z 274.2[M+H]⁺.

2-((1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)amino)pyrimidine-5-carbonitrile(OK)

To a stirred solution of compound OJ (2.3 g, 8.42 mmol) and2-chloropyrimidine-5-carbonitrile (AF, 1.2 g, 8.42 mmol) in EtOH (100mL), DIPEA (3.7 mL, 21.06 mmol) was added and the reaction mixture wasstirred at 80° C. for 2 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in EtOAcand washed with water and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (50%EtOAc/hexane) to afford compound OK (2.5 g, 79.0%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.99 (d, J=8.8 Hz, 1H), 8.64 (d,J=9.6 Hz, 2H), 8.29 (s, 1H), 7.86 (s, 1H), 7.47-7.44 (m, 2H), 7.18 (t,J=8.8 Hz, 2H), 5.67-5.61 (m, 1H), 4.58-4.48 (m, 2H); LC-MS: m/z 377.2[M+H]⁺.

N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-5-(1H-tetrazol-5-yl)pyrimidin-2-amine(OL)

To a stirred solution of compound OK (2.0 g, 5.31 mmol) in DMF (50 mL),NaN₃ (1.03 g, 15.95 mmol), NH₄Cl (0.85 g, 15.95 mmol) and LiCl (0.22 g,5.31) were added in a sealed tube and the reaction mixture was stirredat 100° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The residue was diluted with 1N HCl, aqueouslayer was extracted with 10% MeOH/DCM. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford compound OL (2.2 g, crude) as a light yellow sticky oil which wasused as such for the next reaction. ¹H NMR (400 MHz, DMSO-d6): δ 8.80(brs, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 7.95 (s, 2H), 7.86 (s,1H), 7.50-7.47 (m, 2H), 7.18 (t, J=8.8 Hz, 2H), 5.71-5.64 (m, 1H),4.60-4.51 (m, 2H); LC-MS: m/z 420.1 [M+H]⁺.

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine(176)

To a stirred solution of compound OL (2.2 g, 5.25 mmol) in DCM (100 mL),DFAA (1.82 mL, 15.75 mmol) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was quenched withsaturated NaHCO₃ solution and the product was extracted with DCM. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography (10% MeOH/DCM) to afford racemic 176 (1.0 g, 52%)as an off-white solid.

Chiral Preparative SFC Details for 176(+) and 176(−):

The enantiomers were separated by supercritical fluid chromatography(Chiralpak IG, 250×30 mm, 5μ; Mobile Phase: A-C02; B-0.1% NH3 inMethanol; Gradient Elution 15-30% B in 2 min, 30% B hold 4 min, 30-35% Bin 4 min, 35-45% B in 5 min; Flow rate: 80.0 mL/min) to obtain 176(+)(150 mg) and 176(−) (150 mg).

176(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J=9.2 Hz, 1H), 8.82 (d,J=22 Hz, 2H), 8.31 (s, 1H), 7.86 (s, 1H), 7.64-7.38 (m, 3H), 7.19 (t,J=8.8 Hz, 2H), 5.75-5.68 (m, 1H), 4.57-4.54 (m, 2H); LC-MS: m/z 470.15[M+H]⁺; HPLC: 99.55%; C-HPLC: 99.73% (RT: 6.77); SOR: +52.33, Solvent:Methanol, Path length: 100 mm, Concentration: 0.29 w/v %.

176(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J=9.2 Hz, 1H), 8.82 (d,J=22 Hz, 2H), 8.31 (s, 1H), 7.86 (s, 1H), 7.64-7.38 (m, 3H), 7.19 (t,J=8.8 Hz, 2H), 5.75-5.68 (m, 1H), 4.57-4.54 (m, 2H); LC-MS: m/z 470.15[M+H]⁺; HPLC: 99.65%; C-HPLC: 99.10% (RT: 8.03); SOR: −63.29, Solvent:Methanol, Path length: 100 mm, Concentration: 0.3 w/v %.

Examples 177(+) and 177(−)1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one(177(+) and 177(−))

5-methoxy-3,4-dihydro-2H-pyrrole (ON)

Pyrrolidin-2-one (OM, 20.0 g, 235.00 mmol) was added to dimethyl sulfate(22.8 mL, 235.0 mmol) and the resulting reaction mixture was stirred at60° C. for 16 h. The progress of the reaction was monitored by TLC.After completion of reaction, the reaction mixture was cooled and pouredinto saturated K₂CO₃ solution (200 ml) and stirred for 30 min. Theaqueous layer was extracted with diethyl ether (3×100 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound ON (14.0 g, 60.0%) as a brown liquidwhich was used as such for the next reaction.

1-(2-(4-fluorophenyl)-2-oxoethyl)pyrrolidin-2-one (OP)

To a stirred solution of 2-bromo-1-(4-fluorophenyl)ethan-1-one (CH, 5.5g, 25.0 mmol) in DMF (30 mL), compound ON (5.0 g, 51.0 mmol) was addedat RT and the reaction mixture was stirred at 50° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was diluted with water and extracted withEtOAc (500 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography (60% EtOAc/hexane) to afford compoundOP (4.5 g, 80.0%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ8.10-8.07 (m, 2H), 7.39 (t, J=8.8 Hz, 2H), 4.76 (s, 2H), 3.39 (t, J=7.0Hz, 2H), 2.30 (t, J=8.0 Hz, 2H), 2.04-1.96 (m, 2H); LC-MS: m/z 221.95[M+H]⁺.

(E)-1-(2-(4-fluorophenyl)-2-(hydroxyimino)ethyl)pyrrolidin-2-one (OQ)

To a stirred solution of compound OP (4.5 g, 20.0 mmol) in pyridine (40mL), hydroxylamine hydrochloride (2.8 g, 41.0 mmol) was added and thereaction mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of reaction, thereaction mixture was diluted with EtOAc and washed with 1N HCl solution.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford compound OQ (4.5 g, 94.0%) as an off-whitesolid which was used as such for the next reaction. ¹H NMR (400 MHz,DMSO-d6): δ 11.68 (s, 1H), 7.69-7.66 (m, 2H), 7.21 (t, J=8.8 Hz, 2H),4.49 (s, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.15 (t, J=7.8 Hz, 2H), 1.81-1.74(m, 2H); LC-MS: m/z 237.0 [M+H]⁺.

1-(2-amino-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one (OR)

To a stirred solution of compound OQ (4.5 g, 19.00 mmol) in MeOH (50mL), Pd/C (1.0 g) was added and the reaction mixture was stirred at RTfor 16 h under H₂ balloon pressure. The progress of the reaction wasmonitored by TLC. After completion of reaction, the reaction mixture wasfiltered through celite and washed with MeOH. The filtrate wasconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography (80% EtOAc/hexane) to afford compoundOR (3.5 g, 83.0%) as a light brown sticky solid. ¹H NMR (400 MHz,DMSO-d6): δ 7.42-7.38 (m, 2H), 7.15-7.10 (m, 2H), 4.05 (t, J=7.2 Hz,1H), 3.37-3.27 (m, 2H), 3.18-3.10 (m, 2H), 2.33 (brs, 2H), 2.20-2.09 (m,2H), 1.86-1.79 (m, 2H); LC-MS: m/z 223.05 [M+H]⁺.

2-((1-(4-fluorophenyl)-2-(2-oxopyrrolidin-1-yl)ethyl)amino)pyrimidine-5-carbonitrile(OS)

To a stirred solution of compound OR (2.0 g, 9.0 mmol) in EtOH (30 mL),DIPEA (8.3 mL, 45.0 mmol) was added followed by2-chloropyrimidine-5-carbonitrile (AF, 1.3 g, 9.0 mmol) and the reactionmixture was stirred at RT for 16 h. The progress of the reaction wasmonitored by TLC. After completion of reaction, the reaction mixture wasconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography (40% EtOAc/hexane) to afford compoundOS (2.0 g, 69.0%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ8.83 (d, J=8.8 Hz, 1H), 8.68 (s, 2H), 7.47-7.44 (m, 2H), 7.16 (t, J=8.8Hz, 2H), 5.36-5.30 (m, 1H), 3.54 (d, J=7.6 Hz, 2H), 3.31-3.26 (m, 1H),3.20-3.14 (m, 1H), 2.12 (t, J=8.0 Hz, 2H), 1.82-1.74 (m, 2H); LC-MS: m/z326.10 [M+H]⁺.

1-(2-((5-(1H-tetrazol-5-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one(OT)

To a stirred solution of compound OS (1.5 g, 4.60 mmol) in DMF (15 mL),NaN₃ (1.5 g, 23.0 mmol), NH₄Cl (1.2 g, 23.0 mmol) and LiCl (0.3 g) wereadded and the reaction mixture was stirred at 100° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was concentrated under reduced pressure.The residue was quenched with ice cold water and acidified with 1N HClsolution to pH 3-4. The precipitated solid was filtered, washed withcold water and dried under reduced pressure to afford compound OT (1.5g, 88.0%) as an off white solid which was used as such for the nextreaction. LC-MS: m/z 369.10 [M+H]⁺.

1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one(171)

To a stirred solution of compound OT (1.0 g, 2.70 mmol) in DCM (15 mL),DFAA (0.95 mL, 5.40 mmol) was added and the reaction was stirred at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of reaction, the reaction mixture was diluted with DCM andwashed with water. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography (40% EtOAc/hexane) toafford 177 (0.70 g, 61.5%) as an off-white solid.

Chiral Preparative HPLC Details for 176(+) and 176(−):

The enantiomers were separated by chiral preparative HPLC (ShimadzuPreparative LC, 250×30 mm, 5μ; Mobile Phase: A-n-Hexane; B-0.1% NH₃ inEtOH:MeOH (20:80); Isocratic Elution 50% B; Flow rate: 30.0 mL/min) toobtain 177(+) (80 mg) and 177(−) (80 mg).

177(+): ¹H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J=10.0 Hz, 2H), 8.77 (d,J=8.8 Hz, 1H), 7.65-7.39 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 5.42-5.37 (m,1H), 3.56 (d, J=7.6 Hz, 2H), 3.33-3.29 (m, 1H), 3.23-3.17 (m, 1H), 2.12(t, J=8.0 Hz, 2H), 1.82-1.75 (m, 2H); LC-MS: m/z 419.20 [M+H]⁺; HPLC:95.56%; C-HPLC: 99.04% (RT: 7.40); SOR: +83.75, Solvent: Methanol, Pathlength: 100 mm, Concentration: 0.255 w/v %.

177(−): ¹H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J=11.2 Hz, 2H), 8.77 (d,J=8.8 Hz, 1H), 7.65-7.39 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 5.42-5.37 (m,1H), 3.56 (d, J=7.2 Hz, 2H), 3.33-3.29 (m, 1H), 3.23-3.17 (m, 1H), 2.12(t, J=8.4 Hz, 2H), 1.82-1.75 (m, 2H); LC-MS: m/z 419.15 [M+H]⁺; HPLC:94.35%; C-HPLC: 98.31% (RT: 9.55); SOR: −94.58, Solvent: Methanol, Pathlength: 100 mm, Concentration: 0.275 w/v %.

Examples 79-102, 104-107, and 114

Examples 79-102, 104-107, and 114 were prepared in a manner analogous tothe synthetic processes (and respective appropriate reagents andintermediates) used for the preparation of other compounds exemplifiedherein.

Example 185: Analytical Methods HPLC Method A Specifications

Column: X-Select CSH C18 (4.6×150 mm, 3.5 m)

Mobile Phase A-Acetonitrile; Mobile Phase B-5% Acetonitrile+0.1% Formicacid+water Injection Volume: 5.0 μL; Flow Rate: 1.0 mL/minute

Gradient program: 95% B for 1 min, 95% B to 0% B in 8 minute, hold till12 min, at 15.0 min B concentration is 95% up to 18 min.

HPLC Method B Specifications

Column: X-Bridge C18 (4.6×150 mm, 3.5 m)

Mobile Phase A-Acetonitrile; Mobile Phase B-0.1% Ammonia in water

Injection Volume: 5.0 μL; Flow Rate: 1.2 mL/minute

Gradient program: 98% B to 15% B in 6 min, hold till 8 min, at 9 min Bconcentration is 0% hold up to 12 min, at 14 min B concentration is 98%hold up to 18 min.

SFC Method C Specifications

Column: Chiralpak IA (4.6×250 mm, 5.0 am)

Mobile Phase A-Supercritical CO₂; Mobile Phase B-0.1% Ammonia inmethanol

Flow Rate: 3.0 mL/minute

Isocratic program: 15% B for 10 min.

HPLC Method D Specifications

Column: YMC CIRALART CELLULOSE_SC (4.6×250 mm, 5.0 am)

Mobile Phase A-0.1% TFA in MTBE; Mobile Phase B Isopropyl alcohol

Flow Rate: 1.0 mL/minute

Isocratic program: 10% B for 20 min.

HPLC Method E Specifications

Column: YMC CHIRAL AMYLOSE-SA, 250 mm*4.6 mm, 5u

Mobile Phase:

A: n-HEXANE+0.1% DEA

B: DCM:MeOH (50:50)

Flow rate: 1.0 mL/min

Isocratic: 30% B

SFC Method F Specifications

Column: Chiralpak IA, 250 mm*4.6 mm, 5u

Mobile Phase:

A: CO2

B: 0.1% NH3+Methanol

Flow rate: 3.0 mL/min

Isocratic: 20% B

HPLC Method G Specifications

Column: Chiralpak-IG (4.6×250 mm, 5 μm)

Mobile Phase A-n-Hexane+0.1% TFA; Mobile Phase B-Isopropyl alcohol

Injection Volume: 10.0 μL; Flow Rate: 1.0 mL/minute

Isocratic: 15% B

HPLC Method H Specifications

Column: Chiralpak-IA (4.6×250 mm, 5 am)

Mobile Phase A-n-Hexane+0.1% DEA; Mobile Phase B-Ethanol

Flow Rate: 1.0 mL/minute

Isocratic: 25% B

SFC Method I Specifications

Column: Chiralpak IG, 250 mm*4.6 mm, 5u

Mobile Phase:

A: CO2

B: 0.1% NH3+Methanol

Flow rate: 3.0 mL/min

Isocratic: 50% B

SFC Method J Specifications

Column: Chiralpak IA, 250 mm*4.6 mm, 5u

Mobile Phase:

A: CO2

B: 0.1% NH3+Methanol

Flow rate: 3.0 mL/min

Gradient: 10-40% over 5 min, 40% B for 4 min, 40-10% B over 1 min, hold10% B for 2 min

SFC Method K Specifications

Column: Chiralpak IG, 250 mm*4.6 mm, 5u

Mobile Phase:

A: CO2

B: 0.1% NH3+Methanol

Flow rate: 3.0 mL/min

Gradient: 10-40% over 5 min, 40% B for 4 min, 40-10% B over 1 min, hold10% B for 2 min

HPLC Method L Specifications

Column: YMC CHIRAL AMYLOSE-SA, 250 mm*4.6 mm, 5u

Mobile Phase:

A: n-HEXANE+0.1% DEA

B: DCM:MeOH (50:50)

Flow rate: 1.0 mL/min

Isocratic: 40% B

Example 186: Metalloenzyme Activity

All enzymatic reactions were conducted in duplicate at room temperaturefor 17 hours in a 50 μl mixture containing HDAC assay buffer (50 mMTris-HCl, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% Tween 20, 5 μg BSA), anHDAC substrate, an HDAC enzyme, and a test compound. Compound dilutionwas prepared ten-fold higher than the final concentration of thecompounds with 10% DMSO in HDAC assay buffer and 5 al of the dilutionwas added to a 50 al reaction so that the final concentration of DMSO is1% in all of reactions. After enzymatic reactions, 50 μl of HDACDeveloper was added to each well and the plate was incubated at roomtemperature for an additional 20 minutes. Fluorescence intensity wasmeasured at an excitation of 360 nm and an emission of 460 nm using aTecan Infinite M1000 or Biotek Synergy microplate reader. Thefluorescent intensity data were analyzed using the computer software,Graphpad Prism. In the absence of the compound, the fluorescentintensity (Ft) in each data set was defined as 100% activity. In theabsence of HDAC, the fluorescent intensity (Fb) in each data set wasdefined as 0% activity. The percent activity in the presence of eachcompound was calculated according to the following equation: %activity=(F−Fb)/(Ft−Fb), where F=the fluorescent intensity in thepresence of the compound.

The values of % activity versus a series of compound concentrations werethen plotted using non-linear regression analysis of Sigmoidaldose-response curve generated with the equationY=B+(T−B)/1+10((LogEC50−X)×Hill Slope), where Y=percent activity,B=minimum percent activity, T=maximum percent activity, X=logarithm ofcompound and Hill Slope=slope factor or Hill coefficient. The IC₅₀ valuewas determined by the concentration causing a half-maximal percentactivity.

HDAC1 enzymatic assays contained 0.5 ng HDAC1 and 10 uM of HDACsubstrate. HDAC2 enzymatic assays contained 0.5 ng HDAC2 and 10 uM ofHDAC substrate. HDAC3 enzymatic assays contained 0.4 ng HDAC3/NCOR2 and10 uM of HDAC substrate. HDAC4 enzymatic assays contained 0.02 ng HDAC4and 2 uM of HDAC substrate. HDAC5 enzymatic assays contained 0.5 ngHDAC5 and 2 uM of HDAC substrate. HDAC6 enzymatic assays contained 2 ngHDAC6 and 10 uM of HDAC substrate. HDAC7 enzymatic assays contained 0.05ng HDAC7 and 2 uM of HDAC substrate. HDAC8 enzymatic assays contained 5ng HDAC8 and 2 uM of HDAC substrate. HDAC9 enzymatic assays contained 1ng HDAC9 and 2 uM of HDAC substrate. HDAC10 enzymatic assays contained75 ng HDAC10 and 10 uM of HDAC substrate. HDAC11 enzymatic assayscontained 5 ng HDAC11 and 2 uM of HDAC substrate.

Example 187: Mouse Pharmacokinetics

A dose of 5 mg/kg in an appropriate formulation was administered by oralgavage to fasted male Swiss Albino mice (n=3), and the plasma wascollected at 0, 0.25, 0.5, 1, 2, 4, 8, and 24 h. Plasma levels weremeasured by HPLC/MS/MS methods and the pharmacokinetic parameters weredetermined for individual animals from plasma concentration-time datausing noncompartmental model 200-202 in Phoenix WinNonlin 6.3.

TABLE 1 HDAC6 and HDAC1 activity Human Human HPLC HDAC6 HDAC1 RetentionLC-MS Ex. # IC50 (μM) IC50 (μM) Time (Min)^(a) (M + H) Structure  10.21 >30 9.12 348.05

 2 0.39 >30 9.29 336.05

 3 0.23 >30 5.53 337.05

 4 0.023 >30 8.19 330.1

 5 0.034 >100 8.72 348.1

 6 0.057 >30 8.37 317.95

 7 1.7 >30 9.09 380.1

 8 9 >30 9.19 362

 9 0.038 >30 8.81 350

 10 0.009 >100 8.78 366.03

 11 0.006 >100 8.59 366

 12 0.21 >30 9.22 331.08

 13 0.036 >30 8.88 403.97

 13(+) 0.03 >30 3.74^(c) 404.3  13(−) 0.55 >30 4.72^(c) 404.3 14 >30 >30 9.83 424.07

 15 0.074 >30 8.75 390

 16 0.095 >30 9.21 424.05

 17 0.16 >30 9.04 467.14

 18 0.058 >30 9.19 424.07

 19 0.047 >30 9.26 428.07

 20 0.033 >30 8.44 336

 20(+) 0.021 >30 3.52^(c) 336.3  20(−) >1 >30 7.17^(c) 336.25  210.077 >30 8.23 366.1

 22 0.071 >30 8.83 350.06

 23 0.1 >30 9.23 364.17

 24 0.095 >30 9.11 364

 25 >1 >30 7.19 356.05

 26 0.14 >30 7.45 431 (M − H)

 27 0.074 >30 9.32 336.14

 28 0.61 >30 8.3 296

 29 0.45 >30 8.8 347.95

 30 0.77 >30 7.52 435.05

 31 0.12 >30 7.55 337

 32 0.059 >30 8.46 395.95

 33 0.029 >30 8.69 413.95

 34 0.79 >30 9.15 362

 35 0.17 >30 8.42 441.11

 36 0.064 >30 8.74 362.1

 37 0.18 >30 9.12 426.1

 38 0.029 >30 7.49 429.05

 38(+) 0.015 >30 9.18^(c) 429.3  38(−) 0.32 >30 6.86^(c) 429.1  390.05 >30 8.31 491.05

 40 0.22 >30 9.6 378.05

 41 0.25 >30 9.3 378.1

 42 0.25 >30 9.03 378.05

 43 0.039 >30 8.19 359.95

 44 0.044 >30 8.54 360.15

 45 0.064 >30 9.2 398.15

 46 0.023 >30 8.66 360

 47 0.027 >30 9.43 410.05

 48 0.046 >30 8.01 355.1

 49 0.016 >30 9.36 398.05

 50 0.03 >30 9.07 363.9

 51 0.015 >30 9.03 363.9

 52 0.006 >30 9.46 363.95

 53 0.023 >30 8.94 414

 54 0.022 >30 9.1 413.9

 55 0.02 >30 9.22 413.9

 56 0.006 >100 8.5 347.99

 57 0.015 >100 6.86 347.99

 58 0.04 >30 9.29 398

 59 0.021 >30 8.39 366

 60 0.022 >30 8.61 365.95

 61 0.022 >30 8.6 366

 62 0.008 >30 9.19 382.01

 63 0.088 >30 9.34 416.02

 64 0.028 >30 7.72 410.9

 65 0.39 >30 4.49 331

 66 0.042 >30 9.11 382.01

 67 0.19 >30 7.59 348.95

 68 0.1 >30 8.66 428.05

 69 0.13 >30 7.2 437.05

 70 0.1 >30 9.26 431.95

 71 0.1 >30 9.21 416.08

 72 0.035 >30 8.38 366

 73 0.017 >30 8.97 382

 74 0.019 >30 8.73 384.07

 75 0.038 >30 9.2 432.06

 76 0.014 >30 9.08 382.01

 77 0.028 >30 9.47 378

 78 0.047 >30 9.35 393.1

 78(+) 0.048 >30 7.23 393.1  78(−) 0.42 >30 7.24 393.1  79 0.076 >308.08 455.1

 80 0.023 >30 8.99 382.1

 81 0.21 >30 9.45 432.1

 82 0.035 >30 7.47 409

 83 0.16 >30 7.15 356.05

 84 0.077 >30 9.25 446.15

 85 0.062 >30 9.41 432.05

 86 0.028 >30 9.22 430.05

 87 0.12 >30 9.41 462.05

 88 0.029 >30 9 362.1

 89 0.1 >30 9.39 462

 90 0.035 >30 9.45 378.1

 91 0.021 >30 9.07 382.05

 92

 93 0.043 >30 6.39 384.05

 94

 95

 96 0.058 >30 5.81 351.1

 97 0.034 >30 8.99 368.05

 98 0.016 >30 8.98 368.05

 99-R 0.028 >30 8.63 354.05

 99-S >1 >30 8.66 354.05

100(+) 0.013 >30 347^(d) 354.25

100(−) >1 >30 48^(d) 354.25

101(+) 0.022 >30 11.2^(g) 422.1

101(−) 0.71 >30 9.3^(g) 422.1

102 0.092 >30 8.88 422.05

103(+) 0.016 >30 12.12^(e) 447.15

103(−) 0.65 >30 10.06^(e) 447.15

104

105

106 0.016 >30 8.74 396.35

107

108 0.027 >30 7.66 443.15

109 0.037 >30 8.02 457.05

110 0.028 >30 7.79 455.4

111 0.032 >30 8.07 457.45

112 0.032 >30 8.39 471.15

113 0.021 >30 7.94 443.05

114 0.05 >30 8.19 447.05

115(+) 0.018 >30 9.47^(e) 477.2

115(−) 0.37 >30 10.9^(e) 477.1

116(+) 0.017 >30 13.7^(e) 495.15

116(−) 0.26 >30 11.36^(e) 495.15

117

118 0.072 >30 8.56 511.15

118(+) 0.029 >30 19.55^(d) 511.15 119

120(+) 0.037 >30 6.83^(e) 455.2

120(−) 0.15 >30 5.92^(e) 455.2

121

122(+) 0.031 >30 13.25^(f) 495.15

122(−) 0.84 >30 11.27^(f) 495.15

123(+) 1.1 >30 3.94^(f) 375.1

123(−) 1.1 >30 4.82^(f) 375.1

124

125 0.026 >30 6.25^(b) 443.15

126

127A 0.045 >30 7.68 443.1

127B 0.049 >30 7.79 443.1

128 0.13 >30 8.22 491.15

129 0.25 >30 8.16 491.15

130 0.19 >30 8.28 491.15

131 0.058 >30 8.74 505.1

132 0.083 >30 8.31 505.2

133 0.33 >30 8.23 505.2

134A 0.22 >30 8.93 410.25

134B 0.061 >30 8.93 410.25

135(+)

135(−)

136(+)

136(−)

137(+) 0.041 >30 8.98^(e) 461.15

138(+) 0.075 >30 7.13^(f) 529.6

139(+) 0.033 >30 12.47^(e) 461.2

140(+) 0.058 >30 7.53^(e) 475.05

141(+) 0.13 >30 6.19^(e) 543.15

142(+) 0.035 >30 12.37^(e) 473.15

143(+) 0.053 >30 6.97^(e) 487.15

144(+) 0.16 >30 6.41^(e) 555.2

145(+) 0.041 >30 9.11^(e) 509.1

146(+) 0.14 >30 9.2^(e) 577.15

147(+) 0.018 >30 10.15^(e) 509.15

148(+) 0.019 >30 7.42^(e) 523.2

149(+) 0.2 >30 6.44^(e) 591.1

150(+) 0.023 >30 11.19^(e) 521.1

151(+) 0.085 >30 8.45^(e) 535.15

152(+) 0.28 >30 7.2^(e) 603.1

153(+) 0.02 >30 8.91^(e) 509.1

154(+) 0.26 >30 5.88^(e) 577.05

155(+) 0.05 >30 11.94^(e) 509.15

156(+) 0.076 >30 7.79^(e) 523.15

157(+) 0.44 >30 7.11^(e) 591.05

158(+) 0.051 >30 12^(e) 521.15

159(+) 0.09 >30 7.61^(e) 535.15

160(+) 0.58 >30 7.2^(e) 603.25

161(+) 0.043 >30 7.48 414.10

161(−) 0.87 >30 7.48 414.10

162(+) 0.13 >30 8.76 434.0

162(−) 0.3 >30 8.76 434.0

163(+) 0.11 >30 9.73^(h) 452.15

163(−) 0.41 >30 12.87^(h) 452.1

164(+) 0.11 >30 8.79 525.20

164(−) 0.23 >30 8.79 525.20

165(+) 0.11 >30 8.84 537.15

165(−) 0.16 >30 8.84 537.15

166(+) 0.093 >30 5.21^(f) 407.15

166(−) 0.36 >30 6.06^(f) 407.15

167(+) 0.11 >30 6.15^(k) 475.2

167(−) 0.69 >30 6.66^(k) 475.1

168(+) 0.029 >30 7.64 419

168(−) 0.75 >30 7.64 419

169(+) 0.077 >30 4.27^(i) 433.2

169(−) 1.1 >30 8.49^(i) 433.15

170(+) 0.16 >30 5.75^(k) 501.15

170(−) 1 >30 7.57^(k) 501.2

171(+) 0.23 >30 8.16^(k) 447.15

171(−) 0.59 >30 7.54^(k) 447.15

172(A) 0.32 >30 5.87^(k) 529.15

172(B) 0.086 >30 6.33^(k) 529.15

173(+) 0.024 >30 7.94 445.10

173(−) 0.49 >30 7.95 445.10

174(+) 0.17 >30 8.95 527.1

174(−) 0.11 >30 8.96 527.1

175(+) 0.16 >30 5.18^(i) 470.15

175(−) 1.5 >30 5.85^(i) 470.15

176(+) 0.16 >30 6.77^(k) 470.15

176(−) 1.5 >30 8.03^(k) 470.15

177(−) 0.076 >30 7.4^(l) 419.2

177(+) 0.11 >30 9.55^(l) 419.15

178(−)

178(+)

179

180

181

182

183

184

^(a)HPLC Method A; ^(b)HPLC Method B; ^(c)SFC Method C; ^(d)HPLC MethodD; ^(e)HPLC Method E; ^(f)HPLC Method F; ^(g)HPLC Method G; ^(h)HPLCMethod H; ^(i)HPLC Method I; ^(j)HPLC Method J; ^(k)HPLC Method K;^(l)HPLC Method L

The results in Table 1 demonstrate that compounds of Formula I havepotent activity against HDAC6, and most compounds of Formula I havesignificant selectivity for inhibiting HDAC6 over HDAC1. Selectedexamples were further evaluated for selectivity versus all other HDACisoforms. Table 2 shows that all of the evaluated compounds of Formula Ihave significant selectivity for inhibiting HDAC6 over all otherisoforms of HDAC, with selectivity as high as 5000-fold.

TABLE 2 HDAC selectivity profile of selected examples HDAC Enzyme IC₅₀(μM) Ex 1 2 3 4 5 6 7 8 9 10 11 4 >30 >30 >30 >30 >300.023 >30 >30 >30 >30 >30 5 >100 >30 >30 >30 >300.034 >30 >30 >30 >30 >30 9 >30 >30 >30 >30 >300.038 >30 >30 >30 >30 >30 11 >100 >30 >30 >30 >300.006 >30 >30 >30 >30 >30 13 >30 >30 >30 >30 >300.036 >30 >30 >30 >30 >30  38(+) >30 >30 >30 >30 >30 0.01516.7 >30 >30 >30 >30 62 >30 >30 >30 >30 >30 0.008 >30 >30 >30 >30 >3099-R >30 >30 >30 >30 >30 0.028 >30 >30 >30 >30 >30110 >30 >30 >30 >30 >30 0.028 >30 >30 >30 >30 >30 115(+) >30 >30 >3010.7 >30 0.018 11.9 >30 >30 >30 >30 118(+) >30 >30 >30 >30 >300.029 >30 >30 >30 >30 >30 122(+) >30 >30 >30 8.4 >30 0.03126.7 >30 >30 >30 >30 161(+) >30 >30 >30 >30 >300.043 >30 >30 >30 >30 >30 168(+) >30 >30 >30 13.8 >30 0.02924.4 >30 >30 >30 >30

Comparison Examples were also prepared. Table 3 shows that replacing the1,3,4-oxadiazole of compounds of the disclosure with a 1,2,4-oxadiazoleresults in compounds that show significantly decreased inhibition ofHDAC6 and/or a significant loss of selectivity for HDAC6 over many otherHDAC isoforms. In addition, replacement of the 1,3,4-oxadiazole moietywith a hydroxamic acid moiety, which are common in many known HDACinhibitors, results in a significant loss in selectivity over HDAC1.Taken together, these results demonstrate that the compounds of thedisclosure, characterized by having a 1,3,4-oxadiazole, have surprisingpotency and selectivity for inhibition of HDAC6, and possess thepotential for significant therapeutic utility.

TABLE 3 Comparison Results

G

HDAC1 IC₅₀ (μM) 0.086 >30 >30 >30 HDAC2 IC₅₀ (μM) 13 >30 >30 HDAC3 IC₅₀(μM) 4.1 >30 >30 HDAC4 IC₅₀ (μM) 0.013 >30 >30 HDAC5 IC₅₀ (μM)0.25 >30 >30 HDAC6 IC₅₀ (μM) <0.0015 0.15 2.9 0.21 0.023 HDAC7 IC₅₀ (μM)0.020 >30 >30 HDAC8 IC₅₀ (μM) >30 >30 >30 HDAC9 IC₅₀ (μM) 0.077 >30 >30HDAC10 IC₅₀ (μM) 6.4 >30 >30 HDAC11 IC₅₀ (μM) >30 >30 >30

In addition, several exemplary compounds were administered to mice insingle, oral dose pharmacokinetic experiments. The results in Table 4demonstrate that compounds of the disclosure have advantageouspharmacokinetic profiles. All of the exemplary compounds evaluatedpossess a superior Cmax over that of ricolinostat, a moderatelyselective clinical HDAC6 hydroxamate-based inhibitor. In addition, allbut one of the exemplary compounds evaluated possess a superiorhalf-life over that of ricolinostat.

TABLE 4 Oral, Single Dose Mouse PK Results at 5 mg/kg Example Half-life(h) Cmax (ng/mL) Ricolinostat^(a) 2.7 47  38(+)^(b) 2.7 1111 103(+)^(b)3.2 2373 108^(b) 2.3 2123 109^(b) 3.4 678 110^(b) 4.3 830 113(+)^(b) 3.51357 115(+)^(b) 4.3 656 116(+)^(b) 4.5 1006 118(+)^(b) 23.2 697122(+)^(b) 18.4 2930 142(+)^(b) 4.1 2533 150(+)^(c) 9.3 3388 171(+)^(c)3.3 2593 173(+)^(c) 5.6 2823 ^(a)20% CremEL in H20; ^(b)1% CMC in water;^(c)2% DMSO, 0.2% Tween80, 97.8% of 1% CMC.

INCORPORATION BY REFERENCE

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

1-51. (canceled)
 52. A method of treating a subject suffering from orsusceptible to a metalloenzyme-related disorder or disease, comprisingadministering to the subject an effective amount of a compound ofFormula I:

or a pharmaceutically acceptable salt thereof; wherein A is aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, or alkyl, whereineach A is optionally substituted with 1-3 independent substituents R⁵; Xis NR⁴ or O; each of R¹ and R² is, independently, hydrogen, cyano,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,heteroarylalkyl, heterocycloalkylalkyl,—(CR^(h)R^(i))_(n)-E-NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b),—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), —(CR^(h)R^(i))_(n)-G-SO₂R^(d),—CO₂R^(e), —COR^(f), or —CH₂OR^(f), wherein each R¹ and R² is optionallysubstituted with 1-3 independent substituents R⁵; or R¹ and A togetherwith the atoms to which they are attached form a heterocycloalkyl ringor fused bicyclic ring; R³ is haloalkyl or —OR^(g); R⁴ is hydrogen,alkyl, —(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b),—C(O)(CR^(h)R^(i))_(n)NR^(a)R^(b),—C(O)O(CR^(h)R^(i))_(n)C(O)NR^(a)R^(b), or—(CR^(h)R^(i))_(n)OP(O)(OR^(a))₂; each occurrence of R⁵ is,independently, halogen, cyano, alkyl, haloalkyl, —NR^(a)R^(b),—NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b), —(CH₂)_(n)C(O)NR^(a)R^(b),—(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d), —S(O)₂R^(d), —CO₂R^(e), —COR^(f),—(CR^(e)R^(f))_(n)OR^(f), —OR^(f), or aryl substituted with 0-3independent halogen, —NR^(a)R^(b), —NHSO₂R^(c), —(CH₂)_(n)NR^(a)R^(b),—(CH₂)_(n)C(O)NR^(a)R^(b), —(CH₂)_(n)NR^(d)SO₂R^(d), —S(O)R^(d),—S(O)₂R^(d), —CO₂R^(e), —COR^(f), —(CR^(e)R^(f))_(n)OR^(f), or —OR^(f);or two occurrences of R⁵, together with the atoms to which they areattached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each E isindependently a bond, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;each G is independently heteroaryl or heterocycloalkyl; each occurrenceof R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) is, independently,hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl,haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protecting group whenattached to a nitrogen atom, or an oxygen protecting group when attachedto an oxygen atom; or R^(a) and R^(b) together with the atoms to whichthey are attached form a heterocycloalkyl ring; or R^(e) and R^(f)together with the atoms to which they are attached form a cycloalkylring; or 2 instances of R^(d) together with the atoms to which they areattached form a heterocycloalkyl ring; R^(g) is haloalkyl; and eachoccurrence of R^(h) and R^(i) is, independently, hydrogen, halogen,alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, orheterocycloalkylalkyl.
 53. (canceled)
 54. (canceled)
 55. The method ofclaim 52, wherein the disorder or disease is cancer, a proliferativedisease, a neurodegenerative disease, pain, an autoimmune orinflammatory disorder, an infection, a metabolic disorder, anhematologic disorder, a cardiovascular disease, or a combinationthereof.
 56. (canceled)
 57. The method of claim 52, wherein the disorderor disease is multiple myeloma, melanoma, breast cancer, pancreaticcancer, ovarian cancer, prostate cancer, hepatocellular cancer, renalcancer, leukemia, T-cell lymphoma, cardiac cancer, bone cancer,glioblastoma, neuroblastoma, oral squamous cell carcinoma, urothelialcancer, lung cancer, cervical cancer, rectal cancer, liver cancer,pancreatic cancer, brain cancer, kidney cancer, stomach cancer, skincancer, colon cancer, head and neck squamous cell carcinoma, Burkitt'sLymphoma, esophageal cancer, Hodgkin's lymphoma, bladder cancer, orgastric cancer, or a combination thereof.
 58. The method of claim 52,wherein the disorder or disease is rheumatoid arthritis, spondylitisarthritis, psoriatic arthritis, multiple sclerosis, systemic lupuserythematosus, inflammatory bowel disease, graft versus host disease,transplant rejection, fibrotic disease, Crohn's Disease, type-1diabetes, eczema, psoriasis, sepsis, airway hyperresponsiveness, orulcerative colitis, or a combination thereof.
 59. The method of claim52, wherein the disorder or disease is peripheral neuropathy,chemotherapy induced peripheral neuropathy, diabetic peripheralneuropathy, neuropathy, neuralgia, trigeminal neuralgia, postherpeticneuralgia, autoimmune peripheral neuropathy, Leber's hereditary opticneuropathy, POEMS syndrome, Cattleman disease, pain due to tumorinfiltration, HIV related peripheral neuropathy, post-amputation phantompain syndrome, Charcot-Marie Tooth disease, medication inducedperipheral neuropathy, or a combination thereof.
 60. The method of claim52, wherein the disorder or disease is epilepsy, attention deficitdisorder, depression, anxiety, Alzheimer's disease, Parkinson's Disease,Huntington's Disease, amyotrophic lateral sclerosis, spinal muscularatrophy, essential tremor, central nervous system trauma, multiplesclerosis, Charcot-Marie-Tooth (MCT), cerebral ischemia, stroke, GulfWar Illness, or a combination thereof. 61-69. (canceled)
 70. The methodof claim 52, wherein A is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein each A is optionally substituted with 1-3independent substituents R⁵.
 71. The method of claim 52, wherein each ofR¹ and R² is, independently, hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, —CH₂OR^(f), —(CH₂)_(n)NR^(a)C(O)R^(b), —C(O)NR^(a)R^(b), or—(CR^(h)R^(i))_(n)-E-NR^(d)SO₂R^(d), wherein each R¹ and R² isoptionally substituted with 1-3 independent substituents R⁵.
 72. Themethod of claim 52, wherein R¹ is —(CR^(h)R^(i))_(n)NR^(d)SO₂R^(d). 73.The method of claim 52, wherein R² is hydrogen.
 74. The method of claim52, wherein R³ is haloalkyl.
 75. The method of claim 52, wherein X isNR⁴.
 76. The method of claim 52, wherein the compound is of Formula I-a:

or a pharmaceutically acceptable salt thereof.
 77. The method of claim52, wherein the compound is of Formula I-b:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.
 78. The method of claim 52, wherein the compound is of Formula I-d:

or a pharmaceutically acceptable salt thereof.
 79. The method of claim52, wherein the compound is of Formula I-g:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.
 80. The method of claim 52, wherein the compound is of Formula I-h:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.81. The method of claim 52, wherein the compound is of Formula I-j:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4.
 82. The method of claim 52, wherein the compound is of Formula I-i:

or a pharmaceutically acceptable salt thereof.
 83. The method of claim52, wherein the compound is:N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(2);N-((6-methylpyridin-2-yl)methyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(3);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-phenylethyl)pyrimidin-2-amine(6);N-benzhydryl-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(7);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-N-methylpyrimidin-2-amine(8);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)pyrimidin-2-amine(9);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)pyrimidin-2-amine(11);2-(difluoromethyl)-5-(2-(1-phenylcyclopropoxy)pyrimidin-5-yl)-1,3,4-oxadiazole(12);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine(13);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine(13(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)pyrimidin-2-amine(13(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropyl)pyrimidin-2-amine(14);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(15);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-4-yl)cyclopropyl)pyrimidin-2-amine(16);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(4-(4-fluorophenyl)-1-phenylpiperidin-4-yl)pyrimidin-2-amine(17);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4′-fluoro-[1,1′-biphenyl]-3-yl)cyclopropyl)pyrimidin-2-amine(18);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-phenoxyethyl)pyrimidin-2-amine(19);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(20);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(20(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)ethyl)pyrimidin-2-amine(20(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methoxyethyl)pyrimidin-2-amine(21);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)propyl)pyrimidin-2-amine(22);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)butyl)pyrimidin-2-amine(23);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine(24);5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile(25);1-(4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-(4-fluorophenyl)piperidin-1-yl)ethanone(26);N-(1-cyclohexylcyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(27);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-isopropylcyclopropyl)pyrimidin-2-amine(28);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine(29);2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-1-morpholinoethanone(30);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)ethyl)pyrimidin-2-amine(31);N-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(32);N-(1-(4-(difluoromethoxy)-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(33);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidin-2-amine(34);2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)-N-phenylacetamide(35);N-(cyclopropyl(4-fluorophenyl)methyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(36);N-(4,4-difluoro-1-(4-fluorophenyl)cyclohexyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(37);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide(38);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide(38(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)methanesulfonamide(38(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzenesulfonamide(39);N-(1-(2-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(40);N-(1-(3-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(41);N-(1-(4-methoxyphenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(42);N-(1-(4-bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(47);4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzonitrile(48);N-(1-(2-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(52);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(53);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(54);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(55);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine(58);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,3-difluorophenyl)cyclopropyl)pyrimidin-2-amine(60);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,5-difluorophenyl)cyclopropyl)pyrimidin-2-amine(61);N-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(62);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluoro-2-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine(63);N-(1-(6-bromopyridin-3-yl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(64);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(pyridin-3-yl)cyclopropyl)pyrimidin-2-amine(65);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(5-fluoropyridin-2-yl)cyclopropyl)pyrimidin-2-amine(67);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(68);N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)benzyl)methanesulfonamide(69);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(70);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)pyrimidin-2-amine(71);N-(1-(3-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(73);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4,6-trifluorophenyl)cyclopropyl)pyrimidin-2-amine(74);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-5-(trifluoromethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(75);N-(1-(5-chloro-2-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(76);N-(1-(2-chloro-3-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(77);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide(78);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide(78(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)acetamide(78(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)benzamide(79);N-(1-(2-chloro-5-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(80);N-(1-(2-chloro-5-(trifluoromethyl)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(81);N-(1-(2-bromopyridin-4-yl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(82);4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)cyclopropyl)picolinonitrile(83);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pyrimidin-2-amine(84);N-(1-(2-chloro-3-(trifluoromethyl)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(85);N-(1-(2-chloro-3-(difluoromethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(86);N-(1-(2-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(87);N-(1-(2-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(89);N-(1-(2-chloro-5-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(90);N-(1-(2-chloro-3-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(91);1-(4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-4-isopropylpiperidin-1-yl)ethanone(92);1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-1-(2,4-difluorophenyl)propan-2-ol(93);Ni-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-1-(4-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine(94);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(4-(2,4-difluorophenyl)-1-methylpiperidin-4-yl)pyrimidin-2-amine(95);N1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-1-(4-fluorophenyl)ethane-1,2-diamine(96);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(2,4-difluorophenyl)propan-2-yl)pyrimidin-2-amine(97);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(2-(2,6-difluorophenyl)propan-2-yl)pyrimidin-2-amine(98);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)ethyl)pyrimidin-2-amine(99);5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[(1R)-1-(2,4-difluorophenyl)ethyl]pyrimidin-2-amine(99-R);5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[(1S)-1-(2,4-difluorophenyl)ethyl]pyrimidin-2-amine(99-S);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine(100);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine(100(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)ethyl)pyrimidin-2-amine(100(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-3,3,3-trifluoropropyl)pyrimidin-2-amine(101);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)-3,3,3-trifluoropropyl)pyrimidin-2-amine(102);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(103);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(103(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)methanesulfonamide(103(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,6-difluorophenyl)ethyl)methanesulfonamide(104);N-(1-(2-(difluoromethoxy)-6-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(105);N-(1-(2,6-difluoro-4-methoxyphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(106);N-(1-(2,6-difluoro-4-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(107);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)ethanesulfonamide(108);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-2-sulfonamide(109);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanesulfonamide(110);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)propane-1-sulfonamide(111);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2-methylpropane-1-sulfonamide(112);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide(113);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylmethanesulfonamide(113(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2,2,2-trifluoroacetamide(114);N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(115);(+)-N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(115(+));(−)-N-(2-(4-(difluoromethoxy)phenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(115(−));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(116);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(116(+));(−)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(116(−));N-(2-(4-(difluoromethoxy)-2,6-difluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(117);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(118);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(118(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-2,2,2-trifluoroethanesulfonamide(119);2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine1,1-dioxide (120);(+)-2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine1,1-dioxide (120(+));(−)-2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)isothiazolidine1,1-dioxide (120(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4,6-trifluorophenyl)ethyl)methanesulfonamide(121);N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(122);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(122(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)methanesulfonamide(122(−));N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(123);(+)-N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(123(+));(−)-N-(2-cyclopropyl-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(123(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(tetrahydro-2H-pyran-4-yl)ethyl)methanesulfonamide(124);N-(3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-3-(4-fluorophenyl)propyl)methanesulfonamide(125);5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-((4-fluorophenyl)(1-(methylsulfonyl)azetidin-3-yl)methyl)pyrimidin-2-amine(126);N-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)methanesulfonamide(127);N-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(128);N-(4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(129);N-(2-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)(4-fluorophenyl)methyl)phenyl)methanesulfonamide(130);N-(2-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(131);N-(3-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(132);N-(4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)phenyl)methanesulfonamide(133);N-(2-cyclopropoxy-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(135);(+)-N-(2-cyclopropoxy-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(135(+));(−)-N-(2-cyclopropoxy-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(135(−));N-(2-cyclopropoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(136);(+)-N-(2-cyclopropoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(136(+));(−)-N-(2-cyclopropoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine(136(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide(137);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylmethanesulfonamide(137(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(138);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(138(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide(139);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)ethanesulfonamide(139(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide(140);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylethanesulfonamide(140(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(141);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(141(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide(142);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)cyclopropanesulfonamide(142(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide(143);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-methylcyclopropanesulfonamide(143(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(144);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(2,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(144(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide(145);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylmethanesulfonamide(145(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(146);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(146(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide(147);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)ethanesulfonamide(147(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide(148);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylethanesulfonamide(148(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(149);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(149(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide(150);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)cyclopropanesulfonamide(150(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide(151);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-methylcyclopropanesulfonamide(151(+));N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(152);(+)-N-(2-(4-(difluoromethoxy)-2-fluorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(152(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide(153);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylmethanesulfonamide(153(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(154);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(154(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide(155);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)ethanesulfonamide(155(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide(156);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylethanesulfonamide(156(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(157);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(157(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide(158);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)cyclopropanesulfonamide(158(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide(159);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-methylcyclopropanesulfonamide(159(+));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(160);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(160(+));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine(161);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine(161(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)pyrimidin-2-amine(161(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(162);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(162(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(162(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(163);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(163(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,4-difluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)pyrimidin-2-amine(163(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(164);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(164(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(164(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(165);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(165(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanesulfonamide(165(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(166);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(166(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylacetamide(166(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(167);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(167(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)acetamide(167(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(168);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(168(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)cyclopropanecarboxamide(168(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(169);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(169(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-methylcyclopropanecarboxamide(169(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(170);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(170(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide(170(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(171);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(171(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)methanesulfonamide(171(−));N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172);(+)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172(+));(−)-N-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(3,4-difluorophenyl)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(172(−));N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(173);(+)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(173(+));(−)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)methanesulfonamide(173(−));N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174);(+)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174(+));(−)-N-(2-(4-chlorophenyl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(174(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine(175);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine(175(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl)pyrimidin-2-amine(175(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine(176);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine(176(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine(176(−));1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one(177);(+)-1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one(177(+));(−)-1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2-(4-fluorophenyl)ethyl)pyrrolidin-2-one(177(−));5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(3-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl)pyrimidin-2-amine(178);(+)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(3-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl)pyrimidin-2-amine(178(+));(−)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(4-fluorophenyl)-2-(3-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl)pyrimidin-2-amine(178(−));2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(1-(4-fluorophenyl)cyclopropyl)amino)-N,N-dimethylacetamide(179); fluorophenyl)cyclopropyl)amino)-N,N-diethylacetamide (180);2-(dimethylamino)-2-oxoethyl(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(l-(4-fluorophenyl)cyclopropyl)carbamate(181);2-(diethylamino)-2-oxoethyl(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(1-(4-fluorophenyl)cyclopropyl)carbamate(182);2-amino-N-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)acetamide(183); or((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)(1-(4-fluorophenyl)cyclopropyl)amino)methyldihydrogen phosphate (184); or a pharmaceutically acceptable saltthereof.